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DOI: 10.2337/dc06-2562
© 2007 by the American Diabetes Association
Online Letters: Comments and Responses |
Differences in Glucose Tolerance Between Fixed-Dose Antihypertensive Drug Combinations in People With Metabolic Syndrome
Response to Bakris et al.
1 University of Mississippi Medical Center, Jackson, Mississippi
2 University of Mississippi School of Pharmacy, Jackson, Mississippi
Address correspondence to Daniel M. Riche, PharmD, BCPS, Clinical Assistant Professor, University of Mississippi Medical Center, Department of Pharmacy Practice, Office Annex Building, WW128, 2500 North State St., Jackson, MS 39216. E-mail: driche{at}sop.umsmed.edu
We read with great interest the recent article by Bakris et al. (1). The authors reported that in patients with impaired glucose tolerance (IGT), the combination of losartan and hydrochlorothiazide resulted in an increased rate of new-onset diabetes when compared with trandolapril and verapamil. Indeed, we agree that thiazide diuretics have a history of producing adverse metabolic effects; however, we contend that losartan is an inappropriate angiotensin receptor blocker (ARB) choice. Losartan has inadequate peroxisome proliferator–activated receptor 
(PPAR) activity when compared with the other drugs in its class, limiting its ability to neutralize the detrimental glucose effects of thiazide diuretics (2).
It has been shown that the PPAR activity of thiazolidinediones reduces the risk of new-onset diabetes in patients with IGT (3). Several ARBs have been evaluated for PPAR activity. Specifically, telmisartan has demonstrated PPAR agonism at a much higher rate than losartan in vivo (2). In fact, in vitro studies have shown that telmisartan has 
25% of the PPAR activity of pioglitazone (2). In contrast, losartan fails to demonstrate significant PPAR effect, even at higher concentrations in humans (2). Thus, telmisartan may have been a more favorable choice as a glycemic ARB/thiazide combination than losartan.
Concerning patients with IGT, an ACE inhibitor or ARB is considered the first-line antihypertensive of choice; however, according to current guidelines, two or more antihypertensive medications are typically required to achieve blood pressure goals, and a thiazide diuretic is considered second-line treatment for most (4). The results of the STAR (Study of Trandolapril/Verapamil SR and Insulin Resistance) trial suggest that use of a thiazide diuretic (regardless of ACE inhibitor or ARB) is inappropriate for treating hypertension in patients with IGT, which is corroborated by the findings of a recent prospective cohort (5). This cohort also reported that calcium channel blockers were not associated with an increased onset of symptomatic diabetes, paralleling the STAR trial results (1,5). While higher-affinity PPAR ARBs (i.e., telmisartan) are undergoing studies to assess risk of new-onset diabetes (ONTARGET [Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial] and TRANSCEND [Telmisartan Randomized Assessment Study in ACE-I Intolerant Subjects With Cardiovascular Disease]), alternative ACE inhibitor or ARB combinations (with calcium channel blockers or doxazosin) should be considered before thiazide diuretics as second-line agents in patients with IGT (6).
References
- Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, Bacher P, Sowers J, the STAR Investigators: Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care 29:2592–2597, 2006
[Abstract/Free Full Text] - Benndorf RA, Rudolph T, Appel D, Schwedhelm E, Maas R, Schulze F, Silberhorn E, Boger RH: Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism 55:1159–1164, 2006[Medline]
- DREAM (Diabetes Reduction Assessment With Ramipril and Rosiglitazone Medication) Trail Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105, 2006[Medline]
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, the Joint National Committee on Prevention, Dedection, Evaluation, and Treatment of High Blood Pressure: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206–1252, 2003
[Abstract/Free Full Text] - Taylor EN, Hu FB, Curhan GC: Antihypertensive medications and the risk of incident type 2 diabetes. Diabetes Care 29:1065–1070, 2006
[Abstract/Free Full Text] - Pessina AC, Ciccariello L, Perrone F, Stoico V, Gussoni G, Scotti A, Muggeo M: Clinical efficacy and tolerability of alpha-blocker doxazosin as add-on therapy in patients with hypertension and impaired glucose metabolism. Nutr Metab Cardiovasc Dis 16:137–147, 2006[Medline]
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  G. L. Bakris Differences in Glucose Tolerance Between Fixed-Dose Antihypertensive Drug Combinations in People With Metabolic Syndrome: Response to O'Malley, Bouldin, and Riche Diabetes Care, April 1, 2007; 30(4): e24 - e24. [Full Text] [PDF]
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