Effects of Telmisartan On Metabolic Syndrome Components

Biomedicine & Pharmacotherapy 171 (2024) 116169
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Effects of telmisartan on metabolic syndrome components: a

comprehensive review
Mohsen Imenshahidi a, b, Ali Roohbakhsh a, b, Hossein Hosseinzadeh a, b, *
a
Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
b
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
A R T I C L E I N F O A B S T R A C T
Keywords: Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in
Telmisartan combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers
Hypertension (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer
Diabetes
half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive ac
Obesity
tivity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan,
Hyperlipidemia
Metabolic syndrome valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the
dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full
agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and
PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable
alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes
mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome
and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demon
strated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-
tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. How
ever, larger and long-duration studies are needed to confirm these findings in long-term observational studies
and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.
1. Introduction hyperlipidemia, hypertension, hypercoagulability, obesity, inflamma

tion, and finally atherosclerosis and cardiovascular disease subsequently
1.1. Metabolic syndrome are developed [3,4]. Insulin resistance and hyperglycemia may
contribute to the development of hypertension by activating the
Metabolic syndrome also explained as ”insulin resistance syndrome” renin-angiotensin system (RAS) [5]. Conversely, RAS contributes to the
is a cluster of inter-related abnormalities including insulin resistance, development of insulin resistance and obesity. Therefore it seems that
diabetes, obesity, high blood pressure, and dyslipidemia [1,2]. Among there is a potential causal link among the different components of the
these components, insulin resistance seems to be a central and basic metabolic syndrome [6].
feature of metabolic syndrome, and other disorders including In animal studies, genetic disruption of RAS or administration of
Abbreviations: RAS, Renin-angiotensin system; BMI, Body mass index; RAAS, Renin–angiotensin–aldosterone system; ACEIs, Angiotensin-converting enzyme
inhibitors; ARBs, Angiotensin receptor blockers; AT1, Angiotensin II receptors; PPAR, Peroxisome proliferator-activated receptor; TNF-α, Tumor necrosis factor-α;
CRP, C-reactive protein; HOMA-IR, Homeostasis model assessment of insulin resistance; GLUT-4, Glucose transporter-4; PDX1, Pancreatic duodenal homeobox 1;
AMPK, AMP-activated protein kinase; FABP4, Fatty acid-binding protein 4; ANF, Atrial natriuretic factor; PI3K, Phosphoinositide 3-kinases; Akt, Ak strain trans
forming; NO, Nitric oxide; eNOS, Endothelial nitric oxide synthase; NFκB, Nuclear factor kappa B; VSMCs, Vascular smooth muscle cells; NADPH oxidase, Nico
tinamide adenine dinucleotide phosphate; mTOR, mechanistic target of rapamycin; VCAM-1, Vascular cell adhesion protein 1; IKKβ, Inhibitor of nuclear factor
kappa-B kinase subunit beta; TGF-β1, Transforming growth factor beta 1; HDL, High-density lipoprotein; LDL, Low-density lipoprotein; GFAP, Glial fibrillary
acidic protein; α-MSH, α-Melanocyte-stimulating hormone; HSL, Hormone-sensitive lipase; COX-2, cyclooxygenase-2; SOD, Superoxide dismutase; GSH, Glutathione;
Cat, Catalase; GLP-1, Glucagon-like peptide-1; Il-1β, Interleukin-1 beta; Il-10, Interleukin-10.
* Corresponding author at: Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
E-mail address: [email protected] (H. Hosseinzadeh).
https://doi.org/10.1016/j.biopha.2024.116169
Received 19 November 2023; Received in revised form 4 January 2024; Accepted 11 January 2024
Available online 15 January 2024
0753-3322/© 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
M. Imenshahidi et al. Biomedicine & Pharmacotherapy 171 (2024) 116169
angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor administration of telmisartan in addition to other conventional medi
blockers (ARBs), or even direct inhibitors of renin, prevents insulin cines, significantly improved HOMA-IR levels, reduced plasma glucose
resistance and obesity as well as hypertension; which indicates the po levels, and reduced tumor necrosis factor-α (TNF-α), C-reactive protein
tential role of RAS-related drugs in the treatment of the metabolic syn (CRP), and interleukin-6 (IL-6) levels [14]. In another study in obese
drome. [7,8] Although all studied ARBs are efficient in improving hypertensive patients, telmisartan administration reduced fasting blood
metabolic syndrome, this effect seems to be greater with telmisartan [8]. glucose and blood pressure but could not significantly reduce abdominal
Telmisartan is an ARB with a special pharmacologic profile, obesity [15]. Daily administration of 80 mg telmisartan in HIV-positive
including partial agonistic activity on peroxisome proliferator-activated hypertensive patients, in addition to a significant reduction in diastolic
receptor γ (PPARγ) and the longest half-life among all ARBs [9]. Some and systolic blood pressure, improved lipid profile and insulin resis
animal studies have shown that telmisartan is more effective in tance, and after 3 months of treatment, significantly reduced
improving metabolic syndrome than other ARBs. For example in an endothelin-1, interleukin-18, and cystatin C [16].
animal model of metabolic syndrome (rats fed a high sodium and fat Considering the above and similar animal and clinical studies, the
diet), telmisartan, but not losartan, improved insulin resistance and present study aims to review the evidence for the efficacy of telmisartan
reduced plasma insulin and glucose. Telmisartan also improved lipid in the treatment of insulin resistance, hypertension, diabetes, hyperlip
profile and showed an antihypertensive effect more significantly than idemia and obesity as main components of metabolic syndrome.
losartan. In addition, these effects of telmisartan were reversed by
GSK0660, a PPARδ antagonist [10]. In a high fructose-induced model of
metabolic syndrome in rats, 5 mg/kg of telmisartan, significantly 1.2. Telmisartan
reduced plasma levels of glucose, insulin, cholesterol, and triglycerides,
significantly increased HDL, and significantly decreased blood pressure The Excessive and prolonged activation of the RAS has a primary role
and body mass index (BMI) [11]. in the pathogenesis of hypertension, atherosclerosis, myocardial
Clinical studies in hypertensive patients also have shown that tel infarction, and heart failure [17]. There are two main ways to inhibit the
misartan modifies lipid profiles and insulin sensitivity [12,13]. (Key RAS; the angiotensin-converting enzyme inhibition or direct blocking of
studies, have been summarized in Table 1). For example, in patients the angiotensin receptors. Although the angiotensin-converting enzyme
with coronary heart disease and type 2 diabetes mellitus, 12 weeks of inhibitors act via inhibition of the main enzyme that converts angio
tensin I to angiotensin II, however, other enzymes, including chymase,
Table 1
Summary of key meta-analysis and systematic review evaluating the efficacy of telmisartan in different components of metabolic syndrome.
Type of Analysis Number Patient population Evaluated parameters Compared drugs Major Outcome (s) Reference
of trials
systematic 8 763 hypertensive patients Fasting plasma glucose (FPG); Telmisartan vs other Telmisartan was superior to other ARBs [77]
review and who had either insulin adiponectin; fasting plasma ARBs in reducing FPG levels; and increasing
meta-analysis resistance or diabetic insulin (FPI); Homeostasis adiponectin level
states model assessment of insulin
resistance
(HOMA-IR)
meta-analysis 21 1679 patients with FPG; FPI HOMA-IR; blood Telmisartan vs other telmisartan was superior in improving [78]
obesity, diabetes, pressure ARBs HOMA-IR level; reducing fasting blood
impaired glucose glucose level and fasting insulin level
tolerance, and metabolic and decreasing diastolic blood pressure
syndrome
Meta-analysis 28 5157 hypertensive diastolic blood pressure Telmisartan vs telmisartan provides a greater diastolic [114]
patients enalapril, ramipril and blood pressure control vs enalapril,
perindopril ramipril and perindopril and better
tolerability
Meta-analysis 11 1832 patients Diastolic and systolic blood Telmisartan vs A significant reduction in 24-hour mean [115]
pressure losartan ambulatory Diastolic and systolic blood
pressure with telmisartan vs losartan.
Meta-analysis 9 645 patients IL-6 and TNF-α levels Telmisartan vs control a significant reduction in IL-6 and TNF-α [143]
levels with telmisartan
Meta-analysis 15 651 hypertensive visceral fat area; subcutaneous Telmisartan vs control A significantly lower visceral fat area in [167]
participants with obesity fat area the telmisartan group
retrospective 1 1279 hypertensive dipper status and blood pressure Telmisartan vs telmisartan normalizes the circadian BP [118]
pooled analysis patients (with normal ramipril pattern to a dipper profile than ramipril
sleeping patterns)
Meta-analysis 4 1050 hypertensive the atrial fibrillation (AF) telmisartan vs other the AF recurrence rate was significantly [175]
patients recurrence rate in hypertensive antihypertensive lower in the telmisartan group patients
patients drugs than in the other antihypertensive
drugs-treated patients
A meta-analysis 9 698 hypertensive patients final left ventricular mass telmisartan vs other a significant reduction in final left [176]
and meta- antihypertensive ventricular mass with telmisartan in
regression drugs comparison with other antihypertensive
drugs
Meta-analysis 15 1926 patients with mild to systolic and diastolic blood Telmisartan vs Telmisartan has a better anti- [109]
moderate hypertension pressure losartan hypertensive effect compared to
losartan
Meta-analysis 6 3762 hypertensive systolic and diastolic blood Telmisartan vs no difference was found between [177]
patients pressure valsartan telmisartan and valsartan
Meta-analysis 7 1163 hypertensive systolic and diastolic blood Telmisartan vs telmisartan provides superior control of [178]
patients pressure losartan blood pressure
Meta-analysis 10 546 patients with fasting glucose and glycosylated Telmisartan vs control significant reductions in fasting glucose [13]
metabolic syndrome, hemoglobin and glycosylated hemoglobin
2
also contribute to the production of angiotensin II and ACE is not the adverse effects, including fluid retention (edema), obesity, cardiac
exclusive enzyme. On the other hand, the angiotensin II receptor dysfunction, and ventricular fibrillation. [30] Troglitazone, the first
blockers (ARBs) can counteract all the adverse effects of angiotensin II drug from the full PPARγ agonists of the thiazolidinedione class, showed
that are produced in different ways and by different enzymes by fatal hepatotoxicity and was withdrawn from the market in 2000 [22].
blocking its binding to the type 1 of angiotensin II receptors (AT1) [12]. Rosiglitazone, another member of this class, was also banned in India in
Among commercially available ARBs, telmisartan has the highest 2010 due to its adverse effects on the cardiovascular system and espe
binding affinity for the AT1 receptor and although it’s binding to the cially on lipid profiles [31]. Adiposity, hepatic damage, precipitation of
AT1 receptor is reversible, but shows an insuperable blocking effect heart failure, anemia, peripheral edema, and increased rate of bone
[12]. fracture are adverse effects that are also associated with other thiazoli
Telmisartan has a very low binding affinity for the type 2 of angio dinediones [22]. Unlike other ARBs, telmisartan is considered safe in
tensin II receptors (AT2) (K >10,000 nM) and also a minimal binding to terms of liver toxicity. Telmisartan has been associated with a low rate of
catecholamine, acetylcholine, dopamine, serotonin and histamine [18]. serum aminotransferase elevations (<2%) that in controlled trials was
The elimination half-life of telmisartan is very long, about 24 h, and no higher than with the placebo group. These elevations were transient
consequently has a long-lasting action and sustained reductions of blood and rarely required dose modification [32].
pressure [19]. The lipophilicity of telmisartan is also more than other Therefore, there is a need for a new class of PPARγ ligands with
ARBs that facilitates cell penetration, oral absorption and tissue distri superior therapeutic efficacy but fewer side effects. Accordingly, partial
bution and consequently produces a larger volume of distribution agonists of PPARγ may be a promising option. Partial agonists of PPARγ
(almost 500 L) [19]. More than 90% of telmisartan is excreted through selectively modulate the expression of genes that contribute to insulin
feces, and therefore telmisartan is different from other ARBs that to sensitization while not affecting the genes involved in weight gain and
varying extents have renal excretion [20]. edema; therefore it is expected that they do not have the side effects of
Compared to some other antihypertensive drugs (losartan, valsartan, full agonists [33]. Balaglitazone, a partial PPARγ agonist, compared to
ramipril, atenolol, and perindopril), telmisartan has shown a superior pioglitazone as a full PPARγ agonist, has shown fewer side effects
effect in patients with mild-to-moderate hypertension, especially at the including obesity and edema [34]. There are several other partial PPARγ
end of the dosing interval [12]. In healthy volunteers, it has been shown agonists, (including PAR-1622, PAM-1616 and KR-62980) which
that 80 mg of telmisartan blocks the effects of angiotensin II by about despite preserving the therapeutic effect on diabetes and insulin resis
90% at peak plasma concentrations and after 24 h, about 40% of inhi tance, they have fewer side effects [35].
bition remains [21]. Telmisartan is considered a first-line drug in the Some studies have shown that telmisartan shows partial PPARγ-
management of hypertension either as monotherapy or as a combination agonistic activity and compared to the full PPARγ agonists, has 25–30%
with other antihypertensive drugs and with a great safety profile. It is of maximal efficacy of full agonists [36,37]. Although for other
also used for the prevention of cardiovascular end-organ damages commercially available ARBs, the activation of PPARγ has been also
related to hypertension, including arterial stiffness, left ventricular hy reported, their activities occur at much higher concentrations of ligands
pertrophy, and atrial fibrillation [12]. and are considerably weaker than telmisartan [12,38,39]. Other ARBs
Several studies have shown that telmisartan exerts partial PPARγ- do not affect this type of receptor in the blood concentrations that are
agonist activity. In comparison to the full PPARγ agonists, it activates achieved after usual oral doses. Telmisartan is a pan-agonist of PPAR
25–30% of the PPARγ receptors [22]. PPARγ is a well-established drug and in addition to PPARγ, it activates PPARα and PPARδ to a lesser
target in the management of diabetes, insulin resistance, and metabolic extent [40].
syndrome [23]. PPARs are ligand-activated transcription factors from The partial PPARγ-agonistic effect of telmisartan, which is probably
the superfamily of nuclear hormone receptors which consist of three achievable at therapeutic doses, may give it an extra ability for the
subtypes, including PPARα, PPARβ/δ, and PPARγ [24]. treatment of obesity and diabetes in addition to cardiovascular disease;
PPARγ is the most studied receptor among these subtypes and has an while does not have the safety concerns of full PPARγ agonists [12]. In
essential role in the homeostasis of glucose and lipids [22]. Pioglitazone animal models, some, but not all studies with small interfering RNA
and rosiglitazone are two thiazolidinediones derivatives, with approaches or PPARγ antagonists have shown that the beneficial effects
anti-diabetic properties that exert their therapeutic effects via PPARγ of telmisartan on different components of the metabolic syndrome may
receptors. These drugs restore insulin resistance and improve the lipid be partially dependent on its activity on PPARγ [41–43].
profile of diabetic patients[25]. In addition to glucose lowering prop
erty, activation of PPARγ receptors may also create other therapeutic 1.3. Pharmacokinetic of telmisartan
properties. PPARγ activation has protective and defensive effects on
endothelium via reducing oxidative stress, activation of eNOS, gener Orally administered telmisartan has a bioavailability of 43%, an
ating nitric oxide, and increasing nitric oxide bioavailability [12,22]. elimination half-life of about 24 h, and a mean plasma protein binding of
The activation of PPARγ also increases the production of adiponectin 99.5% in healthy subjects [44]. Telmisartan displays a saturable binding
which leads to an improvement in endothelial function via the activa to the serum albumin and the alpha1-acid glycoprotein [19]. The area
tion of AMPK/eNOS and cAMP/PKA signaling pathways and the under the plasma concentration-time curve (AUC) and the peak con
enhancement of NO bioavailability and a reduction in oxidative stress centration in plasma (Cmax) of telmisartan show a significant
[26]. PPARγ activation prevents the cascade of adhesion and vascular inter-individual variation in both the hypertensive patients and healthy
inflammation through the inhibition of TNF-α-induced recruitment of volunteers [44]. The usual effective dose of telmisartan is 40 mg daily,
monocytic cells and endothelial expression of vascular cell adhesion but there are a significant number of patients who require higher doses
molecule-1 (VCAM-1) in endothelial cells. The inhibitory effect of tel or combination therapy to achieve proper blood pressure control [45].
misartan on monocytic cell recruitment and VCAM-1 induction is Because, all the pharmacokinetic processes of telmisartan, including
attenuated in the presence of the PPARγ antagonist, GW9662. [27] In a absorption, distribution, and excretion show inter-individual variation
clinical study of patients with diabetes and coronary artery disease, [44].
rosiglitazone administration reduced arterial stiffness and inflammatory Telmisartan is not a substrate for the CYP-450 system, and almost all
responses [28]. of the drug is excreted unchanged as the parent drug or as acyl-
In addition, a growing body of evidence demonstrates that activation glucuronide metabolite, into the feces [46]. A small fraction of the
of PPARγ exerts anti-oxidative, anti-inflammatory, and anti- drug is excreted into urine as glucuronide conjugate [47]. A transporter
proliferative activities on vascular walls [29]. from the ATP-binding cassette family (ABCC2; formerly the
On the other hand, full PPARγ agonists are correlated to several multidrug-resistance protein 2 (MRP2)), has an important role in the
3
transport of telmisartan [48]. ABCC2 is highly polymorphic, and it has 5. “metabolic syndrome”
been reported that three common Single Nucleotide Polymorphisms
(SNPs) including G1249A, C-24 T, and C3972T, via a posttranscriptional In total, 745 studies were found and 175 articles were used in this
modification, decrease the transporter function [49,50]. The ABCC2 review. Using these articles, the telmisartan effects on the main com
C-24 T has been reported to alter the transports and pharmacokinetics of ponents of metabolic syndrome including hypertension, diabetes,
various drugs, including mycophenolic acid and irinotecan [51,52]. For obesity, and hyperlipidemia, have been reviewed and the main mech
telmisartan, a study on 48 healthy males showed that ABCC2 C3972T anisms of action of telmisartan summarized and discussed.
polymorphism was associated with the pharmacokinetics variability
after taking telmisartan [44]. In the disposition of telmisartan, some 3. Diabetes mellitus
other transporters including ABCB1 (the multiple drug resistance-1
protein (MDR1)), ABCG2 (the human breast cancer resistance protein Various classes of antihypertensive drugs differ in their glycemic
2 (BCRP2)), and SLCO1B3 (the influx pump of the human organic anion effects. Some antihypertensive medicines, such as beta-blockers and
transporting polypeptide 1B3 (OATP1B3)), have also some role in thiazide diuretics can increase blood glucose levels. In addition, an in
addition to MRP2 [53–55]. OATP1B3 is a main transporter for taking up crease in the rates of new-onset diabetes has also been reported with
telmisartan from plasma into the liver. In the liver, telmisartan is con thiazide diuretics and beta-blockers, but not with dihydropyridine cal
jugated with glucoronate, and this metabolite of telmisartan is again a cium channel blockers, ACEIs, and ARBs [58]. A post hoc subgroup
substrate of OATP1B3 and is excreted into the bile [45]. analysis from the antihypertensive and lipid-lowering Treatment to
In humans, telmisartan is metabolized mostly by uridine Prevent Heart Attack Trial (ALLHAT) compared the glycemic effects of
diphosphate-glucuronosyltransferase (UGT) 1A3 and converted to an amlodipine, chlorthalidone, and lisinopril showed that chlorthalidone
acyl-glucuronide metabolite [47]. The results of a recent study of 188 was associated with the increases in the incidence of new cases of dia
healthy volunteers showed that genetic variants of UGT1A3 are strongly betes and plasma glucose concentrations [59]. On the other hand, some
related to the pharmacokinetics of telmisartan. In this study, UGT1A3 * evidence shows that renin–angiotensin–aldosterone system (RAAS)
2 heterozygous and homozygous men, showed a 64% and 63% reduction blockade via the administration of ARBs and ACEI drugs can prevent
in AUC0-∞ of telmisartan, respectively. Therefore, it seems that the diabetes [60–62]. In a post hoc analysis of the HOPE trial, ramipril
carriers of UGT1A3 * 2 are at an increased risk of insufficient blood markedly reduced the risk of new-onset diabetes in comparison to pla
pressure control of telmisartan due to reduced plasma concentrations. cebo [61]. in a meta-analysis of 13 studies with a totally of 67,000 hy
[45] Four other Uridine diphosphate-glucuronosyltransferases including pertensive patients, ARBs significantly reduced new-onset diabetes
UGT1A1, 1A7, 1A8, and 1A9 have also a minor role in glucuronidation mellitus [62].
of telmisartan [56]. In addition to drug elimination, the difference in In the case of telmisartan, the molecular structure of this drug is very
drug distribution (caused by the variation in binding to plasma proteins) similar to thiazolidinedione drugs, and many reports indicate that tel
can also be the source of the difference in the pharmacokinetics and misartan is a partial agonist of the PPARγ receptors while the other ARBs
plasma concentration of telmisartan. AAG, a major binding protein in do not show such property or exert minimal and incomparable effects
plasma for telmisartan and various basic drugs, is encoded by 2 loci, with telmisartan. [36,37,63,64]. In animal studies, it has been shown
including ORM1 and ORM2, of which ORM1 is the dominant one. that the activation of this pathway has an important role in diabetes,
ORM1, Unlike ORM2, is highly polymorphic, and three common hap dyslipidemia, and metabolic syndrome [65–67]. Therefore, telmisartan
lotypes are present at the ORM1 locus (ORM1 *F2 has 113 A/520 A; may induce special beneficial properties on insulin sensitivity than other
ORM1 *F1 has 113 A/520 G; and ORM1 *S has 113 G/ 520 G) [57]. The ARBs and ACEIs [22].
ORM1 *S genotypes have a stronger binding affinity to the drugs There are several animal studies demonstrate the useful effects of
(including telmisartan), and therefore, it seems that the *S alleles may telmisartan on insulin sensitivity and diabetes [68,69] [70]. For
cause lower plasma concentrations of the free telmisartan. Another ge example, in a study of pre-diabetes rats (Otsuka Long-Evans Tokushima
notype, which has A113G, has been shown to influence the pharmaco Fatty (OLETF)) fed with a high-fat diet, administration of telmisartan
kinetics of telmisartan. After taking telmisartan, the heterozygotes of significantly improved insulin resistance and reversed glucose tolerance.
ORM1 113AG, show a larger AUC and a better antihypertensive effect Telmisartan also reduced the mRNA expression of PPARγ1 and γ2,
compared with the patients who have the wild-type allele [44]. adiponectin, and proinflammatory cytokines. [70] In another study in
Collectively, telmisartan is usually effective in a dose of 40 mg daily, but prediabetic Cohen-Rosenthal diabetic hypertensive rats, telmisartan
a wide inter-individual variation has been reported with the AUC (area increased sensitivity to insulin, improved glucose tolerance, and
under the plasma concentration-time curve) and the C max (the peak reduced fasting insulin levels. These effects were mediated through
concentration in plasma) of telmisartan and a major proportion of pa restoring adiponectin, adiponectin receptor receptors of 1 and 2, PPARγ
tients need higher doses to show sufficient therapeutic responses of coactivator 1α, and glucose translocator 4 [71]. From the clinical aspect,
telmisartan on blood pressure and especially on other components of several clinical studies have investigated the antidiabetic effect of tel
metabolic syndrome. Genotype analysis or determination of plasma misartan and different findings have been obtained [72–74]. In a
concentration of the drug in patients receiving telmisartan can be useful double-blind, randomized study in hypertensive patients with metabolic
to achieve therapeutic goals, especially in terms of metabolic syndrome. syndrome, administration of 80 mg/day of telmisartan, for 3 months
improved fasting glucose, plasma insulin, insulin resistance, and gly
2. Method cosylated hemoglobin insulin and homeostasis while in this study,
administration of losartan (50 mg/day) did not show significant bene
PubMed, Scopus, and EMBASE have been searched from 1998 to ficial effects [72]. In a recent study, 24 weeks of administration of tel
2023 (25 years) using the following keywords: misartan in 99 hypertensive atherosclerotic patients with impaired
fasting glucose, significantly improved the fasting plasma glucose level
1. Diabetes or hypoglycemic or hyperglycemia or antidiabetic or insu in comparison to the amlodipine group. In this study, telmisartan, after
lin or “blood glucose” or antihyperglycemic Hypertension or hypo 24 weeks, also reduced the proportion of new-onset diabetes mellitus
tensive or antihypertensive or “blood pressure” patients or patients with fasting glucose ≥ 100 mg/dL [73]. Another
2. Atherosclerosis or atherogenic study in 36 patients with hypertension and metabolic syndrome showed
3. Overweight or anti-obesity or Obesity that telmisartan significantly decreased serum insulin levels. In this
4. Dyslipidemia or hypertriglyceridemia or "high triglyceride" or "high study, insulin resistance was also assessed by the HOMA-IR model (ho
cholesterol" or hyperlipidemia or hypercholesterolemia meostasis model assessment of insulin resistance) and showed that
4
telmisartan significantly improves insulin resistance [75]. In a clinical under the curve [81].
study of 28 elderly obese patients, comparing the effects of telmisartan It can be concluded that the most available clinical studies favor the
with candesartan and valsartan in improving insulin resistance, showed beneficial preventive and therapeutic effects of telmisartan in the
that telmisartan, but not candesartan and valsartan, significantly management of diabetes and insulin resistance, but the definitive
improved glucose tolerance. In patients who received telmisartan, the confirmation of this issue requires more and larger clinical trials.
hyperinsulin response to glucose loading and HOMA-IR also signifi Diverse mechanisms have been suggested for the glucose-lowering
cantly improved. [76]. A systematic review and meta-analysis in a total effect of telmisartan (Fig. 1). The antioxidant activity is one of these
of 763 hypertensive patients with diabetes compared the considered mechanisms [22]. In the STZ-induced model of diabetic rats,
insulin-sensitizing effect of telmisartan with other ARBs, and showed telmisartan has reduced malondialdehyde and increased catalase, su
that telmisartan is more effective than other ARBs in improving insulin peroxide dismutase, and glutathione levels [82]. Moreover, telmisartan
sensitivity, reducing fast plasma glucose and increasing adiponectin as a partial PPARγ agonist and with the following genomic effects on the
level. In this study, doses of 40 and 80 of telmisartan were used and it expression of the glucose transporter-4 (GLUT-4) gene, may improve
was shown that the dose of 80 is more effective in reducing the fast glucose uptake and increase insulin sensitivity in adipocytes [69]. The
plasma glucose than with the 40 mg dose of telmisartan. The insulin glucose transporter-4 is transferred to the plasma membrane and
resistance also attenuated with 80 mg of telmisartan [77]. Finally, a thereby the glucose uptake is increased [83]. The potency of 10 μM of
systematic review of 21 randomized controlled trials in 1679 patients telmisartan as an activator of PPARγ is similar to 1 μM of troglitazone. In
with impaired glucose tolerance, diabetes, obesity, and metabolic syn addition, T0070907 (2-chloro-5-nitro-N-4-pyridinyl-benzamide as a
drome that compared telmisartan with other ARBs, showed that telmi PPARγ antagonist, can inhibit the telmisartan-induced up-regulation of
sartan was more effective in decreasing fasting blood glucose level, glucose uptake [83]. Also in INS-1 pancreatic β-cells, 10-μM of telmi
improving HOMA-IR, and reducing diastolic blood pressure in com sartan significantly improved insulin secretion and markedly reduced
parison to other ARBs [78]. the protein level of CHOP, GRP78, and caspase 12, and this protective
On the other hand, limited studies are showing that telmisartan does effect was reversed by the coadministartion of a PPARγ blocker
not have significant effects on insulin resistance and diabetes. For (GW9662) that show the effect of telmisartan is mediated at least partly
example, in a prospective, randomized, parallel-group clinical trial, via PPAR-γ signal pathway[84].
administration of 40 mg/day of telmisartan, had no significant effects on Although most studies indicate the role of the PPARγ receptor in the
blood levels of glucose, insulin, adiponectin, and leptin [74]. About the beneficial effects of telmisartan, there is an opinion that underestimates
dose of 80 mg/day of telmisartan, a study in hypertensive patients with the role of the PPARγ receptors to induce a remarkable advantage on
metabolic syndrome also showed that eight weeks of treatment cannot glucose metabolism in clinical situations [85]. This opinion states that
improve the HOMA-IR [79]. In a randomized, double-blind study of 43 although the oral dose of 80 mg/day of telmisartan creates the maximal
schizophrenic patients receiving olanzapine or clozapine, blood concentration of 280 ng/ml, most of the drug is bound to plasma
co-administration of 80 mg per day of telmisartan for 12 weeks did not proteins (plasma protein binding of telmisartan is about 99.5%) and it is
significantly improve HOMA-IR or fasting triglycerides [80]. In 138 estimated that the maximal fraction of unbound protein is between
Overweight/obese patients with waist circumference≥ 35 in. and body 3.3–5.4 nmol. This concentration would be enough to block the AT1
mass index ≥ 28 kg/m2, 16 weeks of administration of telmisartan did receptor, but it is not sufficient to activate PPARγ [85].
not significantly change the insulin sensitivity index or glucose area In addition to PPARγ activation, telmisartan also has an agonistic
Fig. 1. Antidiabetic mechanisms of telmisartan. Schematic illustration of different mechanisms of antidiabetic activity of telmisartan; Telmisartan has a partial
PPARγ-agonistic effect and antagonistic activity on AT1 receptors. Moreover, telmisartan has been reported to have an agonist activity on PPARα and PPARδ re
ceptors. In addition, telmisartan modulates adipokine levels and attenuates oxidative stress.
5
effect on PPARδ receptors [86]. In cultured myotubes, telmisartan via pathway promotes the survival of β cells and inhibits insulin resistance.
PPARδ activation, enhances Glut4 translocation to the plasma mem AMPK promotes glucose metabolism and uptake [103].
brane and increases the phosphorylation of insulin-stimulated Akt and Additionally, in obese mice, telmisartan increases the pancreatic
Akt substrate of 160 kDa. Therefore activation of PPARδ receptors may duodenal homeobox 1 (PDX1) expression and increases the levels of
have some role in the antidiabetic effects of telmisartan [87]. GLP-1 which improves islet glucose sensing and insulin secretion [104].
As mentioned earlier, the RAAS is effective in the development of Pdx1 is a transcription factor involved in the function and survival of
insulin resistance and interruption of the RAAS may improve glycemic pancreatic β-cell [105].
control in diabetic patients [62]. In an animal study in rats, it has been It seems that several mechanisms, especially two main abilities of
shown that activation of AT1 receptors induces β-cell apoptosis and telmisartan, including partial agonism on PPARγ receptors and blockade
autophagy, decreases insulin secretion, and participates in the devel of ATR1 receptors, are involved in the antidiabetic effects of telmisartan.
opment of diabetes. Treatment with telmisartan has restored insulin
secretion and islet dysfunction and attenuated apoptosis and autophagy 4. Hypertension
of β-cells [88]. In another study in rats with long-term high-fat diets, the
inhibition of RAAS protected islet function via reduction of oxidative Hypertension is a major risk factor for cardiovascular disorders and
stress, endoplasmic reticulum stress, and islet inflammation [89]. one of the main components of metabolic syndrome. The ARBs are
Regulation of Adipokines (including adiponectin, resistin, visfatin, highly effective in reducing blood pressure with comparably few side
and TNF-α) in adipocytes has been proposed as another mechanism for effects. Two major advantages of ARBs over ACE inhibitors are that
the antidiabetic effects of telmisartan. Telmisartan was shown clinically ARBs rarely cause cough and angioedema [19]. Telmisartan is one of the
to increase the serum levels of high-molecular-weight adiponectin as the ARBs that the FDA approved it in November 1998, for the treatment of
main bioactive isoform of this hormone [90]. Adiponectin, through hypertension. Among ARBs, telmisartan has the longest duration of ac
activating its receptors, exerts insulin-sensitizing effects and thereby tion (24-hour blood pressure control). In comparison to valsartan, tel
improves glucose metabolism in diabetic patients. In a clinical trial in misartan provides similar renoprotective effects but has a
Fifty hypertensive patients, administration of telmisartan significantly better-improving effect on protein excretion. The results of the
increased the adiponectin concentrations (59.4% increase in compari ONTARGET trial led the FDA to approve telmisartan as the first ARB for
son with baseline levels) [91]. A prospective, open-label, randomized the reduction of cardiovascular risk in patients who cannot receive ACE
study in patients with hypertension and type 2 diabetes also showed that inhibitors [60].
high-dose (80 mg/day), but not low dose (40 mg/day), of telmisartan, Many clinical studies have demonstrated the antihypertensive
improves insulin resistance and increases high-molecular-weight adi properties of telmisartan and have compared its effects versus other
ponectin levels via activation of PPARγ receptors [92]. Regarding the ARBs [106–109]. In the MICARDIS® Community Access Trial (MIC
dose, the results of some studies suggest that the glycaemic control ef CAT-2) in 1619 patients 675 of them had blood pressure that did not
fects of telmisartan are exerted in a dose-dependent manner and for respond to the conventional treatment, and the efficacy of telmisartan
significant improving effects on glucose metabolism, doses more than has been demonstrated. Telmisartan administration (40 mg, and then
40 mg/day may be needed [93]. titrated to 80 mg if needed) successfully controlled the blood pressure in
Tumor necrosis factor-α (TNF-α) is another important adipokine 79% of the patients [108]. A clinical study in 414 hypertensive patients,
involved in the development of insulin resistance and the circulating showed that 40 mg/day of telmisartan is more effective than 80 mg/day
levels of this cytokine are increased in diabetic patients. In a clinical of valsartan in the control of morning blood pressure [110]. A study that
study of 188 patients with diabetes and metabolic syndrome, the compared the duration of action and efficacy of four ARBs (including
administration of telmisartan (40 mg/day), significantly attenuated the candesartan (2–12 mg), losartan (25–100 mg), telmisartan (10–40 mg),
serum levels of TNF-α [94]. It seems that telmisartan could alter the and valsartan (40–80 mg) in Japanese hypertensive patients, showed
TNF-α/adiponectin balance in favor of adiponectin [95]. Telmisartan that telmisartan controls blood pressure longer and better than other
has been shown to decrease the plasma levels of resistin (another adi ARBs [106]. In a randomized, double-blind study in hypertensive pa
pokine that is probably involved in insulin resistance and obesity) in tients, the antihypertensive effect of telmisartan (40- 80 mg) was
diabetic patients [96] as well as in obese mice [97]. Finally, visfatin in compared with valsartan (80–160 mg) for 8 weeks; and the results
another adipokine exerts insulin-sensitizing effects and it has been showed that telmisartan exerts more sustained control on blood pressure
showed that telmisartan increases the visfatin release from adipocytes than valsartan, especially at the final hours of dosing period and in
[98]. patients who have a missed dose [107]. The 24-hour control of blood
The alteration of adipokine levels (increasing the plasma levels of pressure is very important because the incidence of acute myocardial
high-molecular-weight adiponectin and visfatin and decreasing the infarction and other cardiovascular events shows circadian variations
plasma levels of TNF-α and resistin) has some role in the favorable ef with more incidence during the morning (between 06.00 AM and 12.00
fects of telmisartan on diabetes and metabolic syndrome [95]. PM) [111]. The blood pressure also shows a circadian rhythm, being
The attenuating inflammatory response in adipose tissue is another lowest at night, and upon awakening in the morning, suddenly increases
mechanism of telmisartan in restoring insulin resistance. Administration [112]. The duration of action of an optimal antihypertensive drug must
of telmisartan (5 mg/kg/day) in high-fat diet rats, significantly reduced be enough to control blood pressure during the dosing interval and even
serum levels of IL-1β, CRP, and TNF-α and increased serum levels of IL- in case of delayed or missed doses [113].
10 [99]. Also in C57BL/6 J mice fed with a high-fat diet, telmisartan In comparison to ACE inhibitors, telmisartan has better efficacy in
reduced infiltration of T-lymphocyte into adipose tissue [100]. In insulin lowering blood pressure. In one meta-analysis of 28 randomized
resistance caused by obesity, the inflammation of adipose tissue has controlled trials in 5157 patients, telmisartan was compared with
been considered as a first step [99]. different ACE inhibitors (ramipril, perindopril, and enalapril) and
Moreover, telmisartan directly has an inhibitory effect on voltage- showed better blood pressure control and tolerability in hypertensive
dependent potassium channels and opens L-type voltage-gated calcium patients [114]. Another meta-analysis of 11 studies in 1832 patients
channels and increases extracellular Ca (2 +) influx, which in a glucose- showed that telmisartan in comparison with losartan reduces the dia
dependent manner, potentiates insulin secretion. Among ARBs, only stolic and systolic blood pressure [115]. In a Prospective, Randomized
telmisartan has been shown this insulin secretary property in rat islets Investigation in 1613 hypertensive patients, morning administration of
[101]. telmisartan titrated from 40 to 80 mg showed better control of blood
In C2C12 skeletal muscle cells, telmisartan acts directly on skeletal pressure than ramipril with dose titration from 2.5 to 10 mg; especially
muscle AMPK pathways [102]. Activation of the AMPK signaling during the last six hours of the dosing interval (24 h) [116]. In a
6
double-blind clinical trial compared 80 mg/day of telmisartan 80 mg In an animal study in rats, the superiority of telmisartan over val
with 4 mg/day of perindopril, both drugs showed similar results but sartan in less variation in blood pressure and long-lasting blood pressure
telmisartan provided significantly higher reductions in mean diastolic control was attributed to better inhibition of baroreceptor reflex and
blood pressure in the last 8 h of the dosing interval [117]. In a retro sympathetic activity. In this study, telmisartan showed greater antioxi
spective analysis of 1279 patients, 14 weeks of administration of tel dant activity, better amelioration of central oxidative stress, and a
misartan in comparison to ramipril had a greater systolic blood pressure stronger inhibitory effect on central sympathetic output [124].
reduction and better smoothness index [118]. In a study in spontaneously hypertensive rats, telmisartan reduced
Totally in can be concluded that telmisartan generally exerts greater oxidative stress and enhanced NO release via activating the PI3K/Akt
reductions in diastolic and systolic blood pressure than ACE inhibitors pathway. Activation of PI3K leads to Akt phosphorylation, which in turn
especially towards the final hours of the dosing period. In addition, phosphorylates and activates eNOS, enhances NO production attenuates
telmisartan has better tolerability than other ACE inhibitors regarding oxidative stress, and reduces blood pressure [125].
incidences of cough and angioedema [119]. Finally, the last possible mechanism of the antihypertensive property
Besides the block of AT receptors as the main mechanism of the blood of telmisartan is related to the circulating adiponectin. As mentioned
pressure-lowering effect of telmisartan, other mechanisms also play a above, telmisartan increases the circulating adiponectin in diabetic hy
role (Fig. 2). In a study in hypertensive Kazakh patients, it was shown pertensive patients [126]. Adiponectin activates AMPK pathways, pro
that the expression of IL-17 and IL-6 is significantly higher in the blood motes nitric oxide production and thereby exerts antihypertensive
of hypertensive Kazakh patients in comparison with healthy Kazakh activity [127]. Adiponectin also increases the expression of
people. Telmisartan inhibits the proliferation of T lymphocytes and cyclooxygenase-2 via activation of Akt which ultimately leads to the
expression of the Kv1.3 potassium channel in CD4 (+) T lymphocytes of production of prostacyclin (PGI2) and vasodilation activity [127].
these patients which may potentially reduce hypertensive responses
[120]. In addition, telmisartan and other ARBs, decrease the plasma 5. Atherosclerosis
concentration of fatty acid-binding protein 4 (FABP4), an adipokine,
that is elevated in hypertensive patients. This effect of ARBs is not Telmisartan decreases the size of atherosclerotic plaques and pos
related to the blockade of the AT1 receptor in adipocytes [121]. Tel sesses endothelial protective effects through different mechanisms
misartan also stimulates the secretion of ANF through the PPAR-γ re [128]. Acute infusion of angiotensin II increases arterial stiffness as
ceptor activation, which is more potent than rosiglitazone. ANF lowers indicated by an increase in the pulse wave stiffness index and systemic
blood pressure through different mechanisms including diuretic and vascular resistance. Prior administration of telmisartan, attenuates this
vasodilatory effects [122]. effect of angiotensin II [129]. In patients with type 2 diabetes and hy
Moreover, it has been shown that in the rostral ventrolateral medulla pertension, administration of 40 mg/day of telmisartan for 3 weeks
of obesity-prone rats, telmisartan inhibits the sympathetic nervous sys decreased arterial stiffness in the carotid artery[130]. Another study in
tem activity through antioxidant effects. The increased oxidative stress in aged patients with essential hypertension showed that telmisartan
in the rostral ventrolateral medulla of the brainstem activates the sym markedly reduces arterial stiffness and pulse wave velocity and the
pathetic nervous system and causes hypertension [123]. improvement of pulse wave velocity is more than predicted based on the
Fig. 2. Antihypertensive mechanisms of telmisartan. Schematic illustration of different mechanisms of antihypertensive activity of telmisartan; Telmisartan has
antagonistic activity on AT1 receptors and a partial PPARγ-agonistic effect. In addition, telmisartan modulates adipokine levels and attenuates oxidative stress.
Moreover, telmisartan reduces the expression of KV 1.3 voltage-gated potassium channel in lymphocytes. Telmisartan also exerts diuretic activity via reducing
aldosterone secretion and increases the expression of cyclooxygenase-2 via activation of Akt which ultimately leads to the production of prostacyclin and vasodi
lation activity.
7
changes in blood pressure [131]. activation of PPARγ [145,146].

Furthermore, Damage to the endothelium is also involved in It can be concluded that telmisartan possesses an anti-proliferative
atherosclerosis. Endothelial dysfunction disrupts the balance between effect on and exerts protective effects on endothelium via different
vasodilation and vasoconstriction and promotes or exacerbates athero mechanisms, especially through blocking AT1 receptors, PPARγ partial
sclerosis; telmisartan improves endothelial function as shown in the agonistic activity, and antioxidant properties.
Telmisartan versus Ramipril in renal ENdothelial DYsfunction
(TRENDY®) study [132]. In patients with hypertension and micro 6. Lipid profile
albuminuria, the administration of telmisartan (40 mg/day) improved
GFR in response to the administration of l-NMMA which indicates that The lipid-lowering property of telmisartan has been shown both in
telmisartan has improved the endothelial function. Telmisartan also animal and human studies [147–149]. In high-fat diet-induced dyslipi
improved the flow-mediated dilation of brachial artery by 96% in demia in guinea pigs, telmisartan significantly decreased triglyceride
nonhypertensive patients again indicating the improvement of endo and slightly increased the plasma levels of high-density lipoprotein
thelial function [12]. cholesterol (HDL-C) [147]. Human studies in hypertensive patients also
Different mechanisms are involved in the telmisartan-induced have shown that telmisartan improves lipid profiles. For example, in a
improvement of endothelial function. It has been shown in db/db prospective open-label study of 30 newly diagnosed hypertensive pa
mice that telmisartan, significantly ameliorated the downregulation of tients with dyslipidemia, 40 mg/day of telmisartan, for 12 weeks,
phosphor-eNOS and remodeling of the coronary artery. Telmisartan also significantly increased HDL and decreased total cholesterol and tri
exerts anti-inflammatory effects by reducing the activation of vascular glyceride [148]. In 119 type 2 diabetes patients with mild essential
nuclear factor kappa B (NFκB). Coadministration of GW9662, a selective hypertension, telmisartan 40 mg/day for 12 months, was more effective
PPARγ antagonist, with telmisartan, abolished the protective effects of than eprosartan 600 mg/day in reducing total cholesterol, triglycerides,
telmisartan. Therefore, it seems that PPARγ activation is involved in the and low-density lipoprotein (LDL)-cholesterol [149]. In another
vascular protective properties of telmisartan [133,134]. double-blind trial conducted on 116 patients with type 2 diabetes taking
Furthermore, telmisartan via AT1 receptors, inhibits homocysteine- oral hypoglycemic agents, 12 months of administration of telmisartan
induced phosphorylation of PKC, ERK1/2 and Akt in the AFs and (40 mg/day) showed significantly greater reductions in total and LDL
HEK293A cells and thereby improves endothelial function [135]. Tel cholesterol than nifedipine 20 mg/day [150]. In a recent open-label
misartan has also reduced NADPH oxidase activity and superoxide clinical trial in 74 non-alcoholic fatty liver disease patients, adminis
production in apolipoprotein E-deficient mice [128]. tration of telmisartan (20 mg/day) for 8 weeks was as effective as orli
As mentioned above, telmisartan increases eNOS through AMPK stat (120 mg/day) for 12 weeks, in reducing Fasting serum level of free
phosphorylation which improves endothelial function [127]. fatty acid [151].
On the other hand, one study in bovine aortic endothelial cells In terms of the mechanisms of lipid-lowering effect, telmisartan has
directly evaluated the effects of telmisartan on nitric oxide production hepatic partial PPARα agonist activity and therefore, via a PPARα-
and showed that telmisartan inhibits NO production and artery relaxa dependent pathway, increases lipoprotein lipase expression, which can
tion through protein phosphatase 2 A catalytic subunit (PP2Ac)-medi be considered as one of the probable mechanisms of telmisartan’s anti-
ated dephosphorylation of eNOS-Ser. The results of this study may dyslipidemic properties (Fig. 3) [152]. This mechanism has been showed
provide a mechanism that clarifies why telmisartan shows inconsistent in a cell culture study in HepG2 cells. Telmisartan significantly increased
protective effects in the cerebrocardiovascular system of patients with the PPARα mRNA expression and protein synthesis in HepG2 cells and
ischemic stroke [136]. the expression of lipoprotein lipase mRNA and protein in HepG2 cells
Abnormal proliferation of vascular smooth muscle cells (VSMCs) is and co-administration of MK886, a PPARα -specific antagonist, signifi
another confirmed factor for the formation of atherosclerosis. In an cantly inhibited this effect of telmisartan [153].
animal study in rats, telmisartan, via activation of AMPK, reduced basal There might be also some additive effects between ARBs and statins
and PDGF-stimulated proliferation of VSMC, partly via downregulating to induce additional effects on lipid metabolism in dyslipidemic condi
the mTOR/p70S6K signaling pathway in a PPARγ-independent manner tions. For example, in a dyslipidemia model in guinea pigs, 8 weeks of
[137,138]. Another study in human aortic smooth muscle cells treatment with telmisartan plus pitavastatin significantly enhanced the
demonstrated that telmisartan, but not valsartan, inhibits the prolifer efficacy of pitavastatin by reducing the weight of adipose tissue and
ation of human aortic smooth muscle cells. The agonistic effect on adipocyte size and also upregulating the gene expression of PPAR-δ re
PPAR-γ receptors does not have a major role in inhibiting the prolifer ceptor [147]. In a clinical study in patients with mixed dyslipidemia, the
ation of human aortic smooth muscle cells [139]. In an iliac artery effects of ARBs with different capacities in activating peroxisome
restenosis model in rabbit iliac arteries, telmisartan can inhibit neo PPAR-γ in combination with rosuvastatin were evaluated on HDL sub
intimal hyperplasia via the inhibition of the expression of connexin43 fractions, and the results of this study showed that the combination of
[140]. In the vascular wall of spontaneously hypertensive rats, telmi telmisartan with rosuvastatin increased the activity of HDL-Lp-PLA2
sartan, through preventing the TGF-β1/Smad3 signaling pathway and its [154].
antioxidant activity, effectively prevents vascular remodeling [141]. Another mechanism that has been suggested for the cholesterol-
Aortic remodeling in a high-fat diet model in mice, characterized by lowering activity of telmisartan is the inhibition of intestinal choles
structural changes, such as decreased elastin content and fragmentation terol absorption. This property has been shown in a small clinical study
of elastic fibers and an enhanced inflammatory status, can be inhibited in 20 patients with both hypercholesterolemia and hypertension.
by telmisartan. 3 mg/kg/day of telmisartan preserved elastin content, Regarding statins inhibiting cholesterol synthesis, this mechanism of
suppressed over-expression of IL-1β, TNF-α, and MMP-9 and abolished action of telmisartan may have also a role in additive or synergistic ef
aortic dilatation [142]. The results of a meta-analysis of nine random fects of ARBs and statins in lowering cholesterol in hypertensive patients
ized controlled trials, also demonstrate that telmisartan therapy reduces [155].
the vascular inflammatory status via reducing TNF-α and IL-6 levels
[142,143]. 7. Obesity
Telmisartan, independent of PPARγ, and via decreasing expression of
VCAM-1 and IKKβ, ameliorates hyperglycemia-exacerbated vascular In addition to its act on blood pressure, the RAS pathway is also
inflammation [144,145]. In addition, telmisartan represents a promising effective in regulating adipose tissue growth [156]. Angiotensinogen,
strategy for atherosclerosis restenosis-inducing autophagy pathway and the precursor of angiotensin II, is produced mainly in the liver, but the
increases the expression of beclin-1 and the LC3II/LC3I ratio via adipose tissue also produces it and during the development of obesity,
8
Fig. 3. Lipid-lowering mechanisms of telmisartan. Schematic illustration of different mechanisms of lipid-lowering activity of telmisartan; Telmisartan has a
partial PPARγ-agonistic effect that increases the expression of lipoprotein lipase and increases the hydrolysis of triglycerides. In addition, telmisartan modulates the
adipokine levels and attenuates the intestinal absorption of cholesterol.
the production of angiotensin II is up-regulated in adipose tissue and causes hepatic overexpression of the renin-angiotensin system
involved in the regulation of blood pressure and adipose tissue function [157–159]. In addition, Different ARBs, such as telmisartan, olmesartan
[156]. Animal studies in rodent models have demonstrated that obesity and candesartan have attenuated weight gain in experimental studies
Fig. 4. Antiobesity mechanisms of telmisartan. Schematic illustration of different mechanisms of antiobesity activity of telmisartan; Telmisartan has a partial
PPARγ-agonistic effect that induces M2 polarization and the browning of white adipocytes. Telmisartan has an antagonistic activity on AT1 receptors activates the
ACE2/rMAS axis and improves weight control via the activation of the Mas receptors. Moreover, telmisartan preserves leptin transport across the blood-brain barrier
and increases leptin sensitivity and prevents diet-induced obesity. In addition, telmisartan induces the PKA-dependent phosphorylation of perilipin via activation of
PPAR-δ receptors and thereby stimulates lipolysis.
9
[160–162]. [171]. Telmisartan has also shown an anti-inflammatory effect in the

A multicenter, prospective clinical study in 14,200 patients with hypothalamus of C57BL/6 N mice fed with a high-fat diet. Telmisartan
uncontrolled hypertension also showed that 9 months of administration exerts this anti-inflammatory effect via restoration of hypothalamic
of Irbesartan caused a significant weight loss [163]. These antiobesity triglyceride and ceramide levels and also through alkyne oleate distri
effects were found to be class effects of the ARBs and were only observed bution and normalization of TNFα, GFAP, and IL1α levels of the mice
after the administration of high doses of these drugs [164]. A study in with high-fat diet [164]. Telmisartan administration also enhances the
mice who received a high-fat diet showed that telmisartan and losartan, suppression of food intake induced by the alpha-melanocyte stimulating
modulate the hepatic RAS, favoring the ACE2/rMAS axis over the hormone (a neuropeptide of the melanocortin family). Therefore a po
ACE1/AT1 receptor and thereby improving weight control [159]. More tential role for telmisartan in the regulation of hypothalamic feeding is
precisely, this effect of telmisartan and losartan as AT1 antagonists is via melanocortin-related suppression of food intake [172].
mediated via an angiotensin-[1–7]-dependent mechanism. The antiobesity effect of telmisartan is also dependent on the leptin
Angiotensin-[1–7] is an active metabolite of angiotensin II and angio signaling pathway. Leptin is secreted by adipocytes and as a regulatory
tensin I and activates the Mas receptor as an agonist. The activation of peptide, acts at its receptors in the brain and induces anorexia in a
the Mas receptors by angiotensin-[1–7], attenuates diet-induced obesity negative feedback loop. In human obesity, resistance to leptin activity
in rats and the anti-obesity effects of losartan and telmisartan can partly rather than an absence of leptin is the causative agent [164]. Telmi
be related to angiotensin-[1–7]-dependent mechanism [165]. sartan, via restoration of leptin sensitivity, prevents diet-induced obesity
In the case of telmisartan, in addition to the common mechanisms [173]. In high-fat diet-fed mice, telmisartan attenuates leptin resistance
with other ARBs, it exerts its anti-obesity effects through additional by preserving leptin transport across the blood-brain barrier [174].
mechanisms (Fig. 4). Telmisartan, besides its anti-hypertensive proper
ties, has a remarkable activity on adipose tissue function and structure 8. Conclusion
[158]. Telmisartan ameliorates the accumulation of visceral adipose
tissues partially through the activation of the PPARγ receptors. In a Among the RAAS inhibitor drugs, telmisartan is characterized by two
clinical study of 19 patients with hypertension and metabolic syndrome, features including a long duration of action that provides 24-hour blood
the effect of 40 mg/day of telmisartan was compared to 80 mg/day of pressure control and suitable tolerability. The partial agonistic activity
valsartan for 24 weeks and the results of computed tomography (CT) on PPARγ receptors and antagonistic activity on AT1 receptors give
showed that the visceral fat area was significantly reduced in the tel multiple therapeutic benefits to telmisartan including anti-diabetic and
misartan group while the changes were not significant in patients cardiovascular effects. Moreover, telmisartan has been reported to have
received valsartan [166]. A meta-analysis of telmisartan’s effects on an agonist activity on PPARα and PPARδ receptors. In addition, telmi
body fat distribution in a total of 651 participants with overweight/ sartan modulates the adipokine levels (increasing the serum levels of
obesity also showed that telmisartan improves fat distribution and re high-molecular-weight adiponectin and visfatin and decreasing the
duces visceral fat and therefore could be especially useful in obese serum levels of TNF-α and resistin). All these features together make
hypertensive patients [167]. telmisartan an ideal alternative multi-purpose drug for patients with
PPARγ plays an important role in M2 polarization and the browning hypertension, diabetes mellitus, and other cardiovascular disorders as
of white adipocytes. In a study in C57BL/6 J mice, 2 weeks of admin well as for patients with metabolic syndrome. Administration of telmi
istration of telmisartan, increased the expressions of M2 markers and sartan to these patients could improve medication adherence by
browning markers in white adipose tissues at least partly via PPARγ- reducing the pill number and side effects of polytherapy. However, this
mediated M2 polarization [168]. Indeed, telmisartan modulates the needs a more detailed understanding of the molecular mechanism and
polarization of adipose tissue macrophages to an anti-inflammatory M2 clinical efficacy of telmisartan in the treatment of different components
state and decreases the number of M1 macrophages in visceral adipose of metabolic syndrome. Therefore, larger and long-duration studies are
tissues of high-fat-fed mice [67]. needed to confirm these findings in long-term observational studies and
Telmisartan also prevents obesity and adipogenesis through the prospective trials. In addition, the issue of effective dosage to achieve
activation of PPAR-δ (PPAR-delta). these additional properties of telmisartan needs further investigation.
PPAR-δ activates lipolytic pathways and energy uncoupling in some Presently, some studies show telmisartan influences glycemic control in
tissues. The expression of PPAR-δ in 3T3-L1 preadipocytes is signifi a dose-dependent manner and a low dose of telmisartan, 40 mg/kg, has
cantly upregulated by telmisartan. In addition, long-term administration no significant effect on some components of metabolic syndrome
of telmisartan in wild-type mice and hypertensive rats significantly including diabetes mellitus. Doses more than 40 mg/day may be needed
prevents high-fat diet-induced obesity. However, in PPAR-δ knockout for the improvement of glycemic control. More studies are needed to
mice, telmisartan does not show this anti-obesity effect. Mechanistically, determine the optimum dose of telmisartan in metabolic syndrome.
activation of PPAR-δ by telmisartan induces the PKA-dependent phos
phorylation of perilipin. The phosphorylation of perilipin causes the
Ethics approval
translocation of hormone-sensitive lipase from the cytosol to the lipid
droplet that stimulates lipolysis in wild-type mice. This effect of telmi
Not applicable.
sartan is not exerted in PPAR-δ knockout mice [169].
Moreover, a rat model of obesity has also shown that telmisartan
prevents weight gain and metabolic syndrome through the inhibition of CRediT authorship contribution statement
NFKB p65. The inhibition of NFKB p65 can downregulate IL6 secretion
in M1 macrophages [170]. Roohbakhsh Ali: Writing – review & editing, Visualization, Soft
In addition, the anti-obesity effect of telmisartan may be partly ware. Hosseinzadeh Hossein: Writing – review & editing, Supervision,
related to the modulation of the brain levels of angiotensin II. An animal Project administration, Conceptualization. Imenshahidi Mohsen:
study in transgenic rats with a deficiency in brain angiotensinogen Writing – original draft, Methodology, Investigation, Data curation.
showed that these animals had lower weights during a high-calorie diet
compared with standard chow rats. telmisartan (8 mg/kg/day for 3 Declaration of Generative AI and AI-assisted technologies in the
months significantly reduced energy intake and weight gain in normal writing process
rats fed the high-calorie diet, but only to a minor extent in transgenic
rats with a deficiency in brain angiotensinogen. Therefore, lower brain The authors disclose the use of AI and AI-assisted technologies in the
levels of angiotensin II protect rats from developing diet-induced obesity scientific writing process of this paper.
10
Declaration of Competing Interest [21] J. Stangier, C.A. Su, P.N. van Heiningen, T. Meinicke, J.J. van Lier, H. de Bruin, et
al., Inhibitory effect of telmisartan on the blood pressure response to angiotensin
II challenge, J. Cardiovasc. Pharmacol. 38 (5) (2001) 672–685.
The authors declare that they have no known competing financial [22] M.A. Ayza, K.A. Zewdie, B.A. Tesfaye, S.T. Gebrekirstos, D.F. Berhe, Anti-diabetic
interests or personal relationships that could have appeared to influence effect of telmisartan through its partial PPARγ-agonistic activity, Diabetes Metab.
the work reported in this paper. Syndr. Obes. 13 (2020) 3627–3635.
[23] H.A. Pershadsingh, T.W. Kurtz, Insulin-sensitizing effects of telmisartan:
Hossein Hosseinzadeh is an Associate Editor for Phytomedicine and implications for treating insulin-resistant hypertension and cardiovascular
was not involved in the editorial review or the decision to publish this disease, Diabetes Care 27 (4) (2004) 1015.
article. [24] M. Rakhshandehroo, B. Knoch, M. Müller, S. Kersten, Peroxisome proliferator-
activated receptor alpha target genes, PPAR Res. 2010 (2010).
[25] C.J. Tack, P. Smits, Thiazolidinedione derivatives in type 2 diabetes mellitus,
Data Availability Neth. J. Med 64 (6) (2006) 166–174.
[26] W.T. Wong, X.Y. Tian, A. Xu, J. Yu, C.W. Lau, R.L. Hoo, et al., Adiponectin is
required for PPARγ-mediated improvement of endothelial function in diabetic
No data was used for the research described in the article. mice, Cell Metab. 14 (1) (2011) 104–115.
[27] P. Balakumar, S. Kathuria, Submaximal PPARγ activation and endothelial
Acknowledgment dysfunction: new perspectives for the management of cardiovascular disorders,
Br. J. Pharmacol. 166 (7) (2012) 1981–1992.
[28] G. Wang, J. Wei, Y. Guan, N. Jin, J. Mao, X. Wang, Peroxisome proliferator-
The authors thank the Vice-Chancellor of the Mashhad University of activated receptor-gamma agonist rosiglitazone reduces clinical inflammatory
Medical Sciences, Mashhad, Iran. responses in type 2 diabetes with coronary artery disease after coronary
angioplasty, Metabolism 54 (5) (2005) 590–597.
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H599–H607.
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