Response to Distinct Metabolic Effects of Different Classes of Antihypertensive Drugs
We thank Koh1 for the comment on our recent work, the Mechanisms for the Diabetes Preventing Effect of Candesartan Study.2 Our data suggest adverse effects of thiazide diuretics on glucose metabolism and body fat distribution, whereas an angiotensin receptor blocker (ARB), candesartan, did not differ from placebo in these aspects. We agree that alterations in adipokines, such as leptin and adiponectin, together with inflammatory mediators, may potentially be important players in metabolic and endothelial dysfunction triggered via the renin-angiotensin system (RAS).1,3 However, the role of leptin in vascular and metabolic regulation is very complex, and in our study leptin, as well as adiponectin, levels did not differ between the treatments.2 In this context, it is of interest that the RAS itself is part of a neuroendocrine pathway that can significantly contribute to the early development of insulin resistance and type 2 diabetes mellitus.4 Other than the well-known actions of the RAS in the vasculature, there are multiple effects in the central nervous system, skeletal muscle, liver, and adipose tissue that may interfere with insulin action. Thus, RAS dysregulation might be involved in the primary evolution of insulin resistance, and RAS blockade could potentially help to prevent future type 2 diabetes mellitus development.
Koh’s3 and our2 studies encourage further work to address possible clinical benefits of ARB treatment in comparison with other antihypertensives. One interesting aspect is the potential ability of ARBs to reverse detrimental effects of elevated angiotensin II in inflamed tissues, such as adipose, liver, and vessel walls, that can contribute to metabolic and vascular dysfunction. Combination therapies need further investigation and, as pointed out by Koh,1 regimens targeting multiple pathways seem attractive. For example, adverse metabolic effects of thiazides mediated via RAS activation may be mitigated by simultaneous RAS blockade with an ARB. Other than glucose and lipid variables, such studies should include key measures of inflammation, eg, high-sensitive C-reactive protein, and of vascular dysfunction, eg, urinary albumin excretion rate. Interestingly, in our study, there were signs of elevated e-selectin and adhesion molecules in blood after thiazide treatment suggesting alterations in endothelial function (unpublished data).
The recommendation to use thiazide diuretics as a first-line choice for treatment of hypertension may be challenged, particularly in diabetes mellitus-prone subjects. However, the prevailing guidelines are not likely to be changed unless large-scale outcome studies unequivocally demonstrate meaningful differences in clinical end points. There is ongoing work that addresses ARB effects on type 2 diabetes mellitus development in high-risk individuals,5 but additional long-term investigations are needed. Detailed investigations of metabolic effects of ARBs and thiazides in patients with established type 2 diabetes mellitus are also warranted.
J.W.E. is currently employed by AstraZeneca R&D.
Koh KK. Distinct metabolic effects of different classes of antihypertensive drugs. Hypertension. 2009; 53: e26.
Eriksson JW, Jansson PA, Carlberg B, Hägg A, Kurland L, Svensson MK, Ahlström H, Ström C, Lönn L, Ojbrandt K, Johansson L, Lind L. Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study. Hypertension. 2008; 52: 1030–1037.
Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Koh Y, Shin EK. Distinct vascular and metabolic effects of different classes of anti-hypertensive drugs. Int J Cardiol. 2008; doi:10.1016/j.ijcard.2008.11.017.
Califf RM, Boolell M, Haffner SM, Bethel MA, McMurray J, Duggal A, Holman RR, for the NAVIGATOR Study Group. Prevention of diabetes and cardiovascular disease in patients with impaired glucose tolerance: rationale and design of the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial. Am Heart J. 2008; 156: 623–632.