Published online before print March 27, 2006, doi: 10.1161/01.HYP.0000215184.00915.62
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(Hypertension. 2006;47:822.)
© 2006 American Heart Association, Inc.
Editorial Commentaries |
Telmisartan
The ACE of ARBs?
From the Michael G. deGroote of Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada.
Correspondence to Arya M. Sharma, McMaster University, Hamilton General Hospital, 237 Barton St East, Hamilton, Ontario, Canada, L8L 2X2. E-mail sharma{at}ccc.mcmaster.ca
In 2002, my colleagues and I1 suggested that blockade of the renin-angiotensin system may prevent diabetes by promoting adipogenesis, thereby allowing redistribution of fat from dangerous visceral and ectopic fat deposits to less-dangerous subcutaneous depots. This hypothesis was based on our observation that angiotensin II inhibits human preadipocyte differentiation.2 We subsequently demonstrated increased activity of the renin-angiotensin system in obesity3 and suggested, therefore, that renin-angiotensin blockade should be the treatment of choice in obesity-related hypertension.4
In 2004, Benson et al5 reported the novel observation that the highly lipophilic angiotensin receptor blocker (ARB) telmisartan may directly stimulate the peroxisome proliferator activated receptor 
(PPAR), a key inducer of adipocyte differentiation. Although this property has since been also reported for irbesartan6 and a losartan metabolite,7 there is no doubt that telmisartan by 1 order of magnitude is the most powerful stimulator of PPAR activity among the ARBs. Because thiazolidinediones, a class of even more potent PPAR agonists ("glitazones"), are widely used as insulin sensitizers in the treatment of type 2 diabetes mellitus and promote both adipocyte proliferation and fat redistribution, the report that telmisartan may have similar glitazone-like properties led to widespread and enthusiastic speculations regarding the possible metabolic benefits of this compound.8 Without doubt, such a "eumetabolic" property of an antihypertensive drug would be of considerable interest, given that the majority of patients with hypertension also have other features of the metabolic syndrome. including abdominal adiposity, dyslipidemia. and insulin resistance.
In this issue of Hypertension, Sugimoto et al9 provide further experimental evidence that telmisartan may indeed have a unique advantage over other ARBs in its ability to decrease adipocyte cell size, reduce hepatic fat storage, and increase energy expenditure, effects that the authors largely attribute to its ability to act as a partial PPAR agonist. Compared with valsartan, treatment of rats fed a high-fat, high-carbohydrate diet resulted in significant improvements in metabolic parameters and overall changes compatible with the idea that increased formation of smaller fat cells may have reduced ectopic fat deposition. However, whereas telmisartan may be superior to valsartan in producing these effects, similar metabolic improvements, reduction in adipocyte cell size, and a trend toward reduction in intramyocellular lipids have been reported previously in the fructose-fed rat model of insulin resistance using both the angiotensin-converting enzyme inhibitor temocrapril and the ARB olmesartan.10 Thus, it is not clear that the observations reported in the present study are entirely attributable to PPAR activation by telmisartan, but may in part be mediated through more potent angiotensin blockade.
Interestingly, in this study, telmisartan also reduced weight gain, increased total energy expenditure, and increased expression of key mitochondrial enzymes (cyclooxygenase-1 and mitochondrial transcription factor A) in skeletal muscle.9 This observation is of substantial interest, because there is increasing evidence implicating mitochondrial dysfunction as a key player in the development of obesity, insulin resistance, and type 2 diabetes mellitus associated with sedentariness and aging.11 Thus, for example, the PPAR coactivator 1
, a key determinant of adaptive thermogenesis, the regulated production of heat by burning calories in adipose tissue and skeletal muscle by stimulating the generation of mitochondria and oxidative phosphorylation, has been found to be expressed at lower levels in the healthy relatives of people with insulin resistance and diabetes.12 Indeed, a host of factors and pathways that can potentially affect thermogenesis and mitochondrial function have been suggested to play an important role in the pathogenesis of obesity, insulin resistance, and the metabolic syndrome. These include the steroid receptor coactivator family, the nuclear receptors PPARß/
, thyroid hormone receptors, estrogen-related receptors, protein kinase A, calcium/calmodulin-dependent protein kinase IV, p38 mitogen-activated protein kinase, and cyclin-dependent kinase 9 (reviewed in Reference 13). It is, therefore, not surprising that increasing mitochondrial activity has been suggested as a potential target to prevent and treat obesity and the metabolic syndrome. Physical activity and dietary restriction, the cornerstones of clinical management of the metabolic syndrome, are already known to enhance mitochondrial activity. The suggestion that telmisartan may similarly increased mitochondrial activity clearly deserves further exploration, particularly if the present findings can be confirmed in humans.
Unfortunately, there remains a dearth of information on the metabolic effects of telmisartan or other ARBs from human studies. In fact, the PPAR activating effect of telmisartan has yet to be demonstrated in human cells, a matter of substantial interest because there are important differences in the function of the adipocyte tissue renin-angiotensin system between rodents and humans.14 Thus, for example, the angiotensin II type 2 receptor, which is highly expressed on murine adipocytes and has been shown to mediate some of the proadipogenic effects of angiotensin II in murine cell lines, is virtually absent in humans. Currently, apart from the well-documented ability of angiotensin blockade in general to reduced the incidence of type 2 diabetes mellitus,15 the potential effects of ARBs on insulin resistance and other metabolic parameters remains controversial.4 In fact, there are a number of putative mechanisms, independent of any possible adipocyte-tissue effects, that may explain why blockade of the renin-angiotensin system prevents diabetes (Table).
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Whether or not the PPAR modulating effects of telmisartan discovered by Sugimoto et al9 will translate into greater cardiovascular and metabolic protection with this agent will certainly be the focus of much speculation until conclusive answers from clinical trials become available. A study on the effect of telmisartan on intramyocellular lipids, liver fat, and adipocyte cell size in individuals with abdominal obesity is currently underway (http://www.ClinicalTrials.gov, identifier: NCT00147264), as is a large outcome trial with this compound (ONTARGET). In the meantime, studies like the one by Sugimoto et al9 will continue to foster the discussions on the potential benefits of renin-angiotensin blockade in individuals with abdominal obesity and the metabolic syndrome.
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Acknowledgments |
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A.M.S. is supported by grants from the Canadian Institutes of Medical Research and the Heart and Stroke Foundation of Ontario and holds a Canada Research Chair (Tier 1).
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
A.M.S. has received speaker honoraria, consulting fees, and/or research funding from several makers of angiotensin receptor blockers, including Boehringer-Ingelheim, Merck, Novartis, Sanofi-Aventis, and AstraZeneca.
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References |
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 Top References |
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1. Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertension. 2002; 40: 609–611.
2. Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM. Mature adipocytes inhibit in vitro differentiation of human preadipocytes via angiotensin type 1 receptors. Diabetes. 2002; 51: 1699–1707.
3. Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005; 45: 356–362.
4. Sharma AM. Is there a rationale for angiotensin blockade in the management of obesity hypertension? Hypertension. 2004; 44: 12–19.
5. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, Qi N, Wang J, Avery MA, Kurtz TW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPAR–modulating activity. Hypertension. 2004; 43: 993–1002.
6. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor- activity. Circulation. 2004; 109: 2054–2057.
7. Berger JP, Petro AE, Macnaul KL, Kelly LJ, Zhang BB, Richards K, Elbrecht A, Johnson BA, Zhou G, Doebber TW, Biswas C, Parikh M, Sharma N, Tanen MR, Thompson GM, Ventre J, Adams AD, Mosley R, Surwit RS, Moller DE. Distinct properties and advantages of a novel peroxisome proliferator- activated protein {} selective modulator. Mol Endocrinol. 2003; 17: 662–676.
8. Yamagishi S, Takeuchi M. Telmisartan is a promising cardiometabolic sartan due to its unique PPAR--inducing property. Med Hypotheses. 2005; 64: 476–478.[CrossRef][Medline]
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9. Sugimoto K, Qi NR, Kazdova L, Pravenec M, Ogihara T, Kurtz TW. Telmisartan but not valsartan increases caloric expenditure and protects against weight gain and hepatic steatosis. Hypertension. 2006; 47: 1003–1009.
10. Furuhashi M, Ura N, Takizawa H, Yoshida D, Moniwa N, Murakami H, Higashiura K, Shimamoto K. Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens. 2004; 22: 1977–1982.[CrossRef][Medline] [Order article via Infotrieve]
11. Auwerx J. Improving metabolism by increasing energy expenditure. Nat Med. 2006; 12: 44–45.[CrossRef][Medline] [Order article via Infotrieve]
12. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A. 2003; 100: 8466–8471.
13. Houten SM, Auwerx J. PGC-1: turbocharging mitochondria. Cell. 2004; 119: 5–7.[CrossRef][Medline]
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14. Engeli S, Schling P, Gorzelniak K, Boschmann M, Janke J, Ailhaud G, Teboul M, Massiera F, Sharma AM. The adipose-tissue renin-angiotensin-aldosterone system: role in the metabolic syndrome? Int J Biochem Cell Biol. 2003; 35: 807–825.[CrossRef][Medline] [Order article via Infotrieve]
15. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab. 2004; 30: 487–496.[Medline] [Order article via Infotrieve]
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