The Study of Micardis (telmisartan) in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) compared hydrochlorothiazide (HCTZ) plus telmisartan or valsartan fixed-dose combination therapies on early morning blood pressure (BP), using ambulatory BP monitoring (ABPM).
SMOOTH was a prospective, randomized, open-label, blinded-endpoint, multicentre trial. After a 2- to 4-week, single-blind, placebo run-in period, patients received once-daily telmisartan 80 mg or valsartan 160 mg for 4 weeks, with add-on HCTZ 12.5 mg for 6 weeks (T/HCTZ or V/HCTZ, respectively). At baseline and week 10, ambulatory blood pressure (ABP) was measured every 20 min and hourly means were calculated. The primary endpoint was change from baseline in mean ambulatory systolic and diastolic blood pressure (SBP; DBP) during the last 6 hours of the 24-hour dosing interval.
In total, 840 patients were randomized. At week 10, T/HCTZ provided significantly greater reductions versus V/HCTZ in the last 6 hours mean ABP (differences in favour of T/HCTZ: SBP 3.9 mm Hg, p < 0.0001; DBP 2.0 mm Hg, p = 0.0007). T/HCTZ also produced significantly greater reductions than V/HCTZ in 24-hour mean ABP (differences in favour of T/HCTZ: SBP 3.0 mm Hg, p = 0.0002; DBP 1.6 mm Hg, p = 0.0006) and during the morning, daytime and night-time periods (p < 0.003). Both treatments were well tolerated.
In high-risk, overweight/obese patients with hypertension and type 2 diabetes, T/HCTZ provides significantly greater BP lowering versus V/HCTZ throughout the 24-hour dosing interval, particularly during the hazardous early morning hours.
Hypertension, obesity and type 2 diabetes are cardiovascular risk factors that commonly occur together. Insufficient suppression of the renin-angiotensin-aldosterone system (RAAS) has been implicated in the development of obesity-related high arterial pressure, and is linked with insulin resistance and type 2 diabetes 1,2. RAAS blockade may, therefore, be particularly beneficial in the antihypertensive treatment of patients with type 2 diabetes, features of metabolic syndrome and obesity, particularly as this population is poorly controlled. In a cross-sectional prevalence study of 45,125 subjects from Germany, hypertension (blood pressure [BP] ≥ 140/90 mm Hg) was twice as common in obese as in non-obese patients (60.6 vs. 34.3%, respectively) 3. Furthermore, BP control in diagnosed and treated obese hypertensive patients was extremely low (overall response [OR] = 0.8).
Adequate BP control is also overlooked during the morning hours. During this time there is typically a surge in BP, which is associated with a high incidence of cerebro- and cardiovascular events 4. Consequently, the early morning hours are an important therapeutic target for antihypertensive treatment 5.
Telmisartan is a once-daily angiotensin II receptor blocker (ARB) with the longest plasma half-life of any ARB, providing 24-hour coverage of BP control from a single daily dose; the angiotensin type 1 (AT1) versus AT2 receptor affinity ratio for telmisartan is 3000-fold; however, it is higher for valsartan (about 20,000-fold) 6-8. In two randomized studies of 1,279 hypertensive patients, telmisartan 80 mg significantly reduced the early morning systolic BP (SBP) surge compared with ramipril 10 mg 9. Another ARB, valsartan has been shown to improve obesity-related disorders, reduce body mass index (BMI) and lower BP 10. Based on such findings, it is therefore relevant to compare telmisartan with valsartan. A previous pooled analysis of two studies in patients with uncomplicated hypertension showed that telmisartan 80 mg provided SBP reductions in the last 6 hours of the dosing interval and in the 24-hour mean that were superior to the equipotent valsartan 160 mg (by 2.7 and 2.0 mm Hg, respectively) 11. In addition, two recent studies have shown that telmisartan 80 mg plus hydrochlorothiazide (HCTZ) 25 mg was superior to valsartan 160 mg plus HCTZ 25 mg 12,13. However, there are few studies comparing telmisartan and valsartan when used in combination with low-dose HCTZ 12.5 mg, and few direct ARB comparisons in obese hypertensive patients with type 2 diabetes./>/>/>/>/>
- Rahmouni K, Correia ML, Haynes WG, Mark AL: Obesity-associated hypertension: new insights into mechanisms. Hypertension 2005, 45:9-14.
- Sharma AM: Is there a rationale for angiotensin blockade in the management of obesity hypertension? Hypertension 2004, 44:12-19.
- Bramlage P, Pittrow D, Wittchen HU, Kirch W, Boehler S, Lehnert H, Hoefler M, Unger T, Sharma AM: Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens 2004, 17:904-910.
- Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP, Hier DB, Wolf PA, Caplan LR, Foulkes MA: Morning increase in onset of ischemic stroke. Stroke 1989, 20:473-476.
- Kario K: Time for focus on morning hypertension: pitfall of current antihypertensive medication. Am J Hypertens 2005, 18:149-151.
- Burnier M, Maillard M: The comparative pharmacology of angiotensin II receptor antagonists. Blood Press Suppl 2001, 1():6-11.
- Kakuta H, Sudoh K, Sasmata M, Yamagishi S: Telmisartan has the strongest binding affinity to angiotensin II type 1 receptor: comparison with other angiotensin II type 1 receptor blockers. Int J Clin Pharmacol Res 2005, 25(1):41-46.
- Wienen W, Entzeroth M, van Meel JCA, Stangier J, Busch U, Ebner T, Schmid J, Lehmann H, Matzek K, Kempthorne-Rawson J, Gladigau V, Hauel HH: A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardiovasc Drug Rev 2002, 18:127-156.
- Gosse P, Neutel JM, Schumacher H, Lacourci─é┬¿re Y, Williams B, Davidai G: The effect of telmisartan and ramipril on early morning blood pressure surge: a pooled analysis of two randomized clinical trials. Blood Press Monit 2007, 12:141-147.
- Fogari R, Derosa G, Zoppi A, Rinaldi A, Lazzari P, Fogari E, Mugellini A, Preti P: Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients. Hypertens Res 2005, 28:209-214.
- Lacourci─é┬¿re Y, Krzesinski JM, White WB, Davidai G, Schumacher H: Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit 2004, 9:203-210.
- White WB, Punzi HA, Murwin D, Koval SE, Davidai G, Neutel JM: Effects of the angiotensin II receptor blockers telmisartan vs valsartan in combination with hydrochlorothiazide 25 mg once daily for the treatment of hypertension. J Clin Hypertens (Greenwich) 2006, 8(9):626-633.
- White WB, Guthrie R, Chrysant SG, Murwin D, Davidai G, Koval S: A second large trial of Telmisartan and HCTZ (80/25 mg) shows a larger antihypertensive effect than Valsartan and HCTZ (160/25 mg). J Clin Hypertens 2007, 9(Suppl A):A44. (Abstract P-94)
- Smith DH, Neutel JM, Lacourci─é┬¿re Y, Kempthorne-Rawson J: Prospective, randomized, open-label, blinded-endpoint (PROBE) designed trials yield the same results as doubleblind, placebo-controlled trials with respect to ABPM measurements. J Hypertens 2003, 21:1291-1298.
- American Diabetes Association: Treatment of hypertension in adults with diabetes. Diabet Care 2002, 25:199-201.
- 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 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 2003, 289:2560-2572.
- Sharma AM, Bramlage P, Kirch W: Antihypertensive effect of irbesartan and predictors of response in obesity-associated hypertension: a prospective, open-label study. Clin Drug Investig 2005, 25:765-776.
- Jordan J, Engeli S, Boschmann M, Weidinger G, Luft FC, Sharma AM, Kreuzberg U: Hemodynamic and metabolic responses to valsartan and atenolol in obese hypertensive patients. J Hypertens 2005, 23:2313-2318.
- Grassi G, Seravalle G, Dell'Oro R, Trevano FQ, Bombelli M, Scopelliti F, Facchini A, Mancia G: Comparative effects of candesartan and hydrochlorothiazide on blood pressure, insulin sensitivity, and sympathetic drive in obese hypertensive individuals: results from the CROSS study. J Hypertens 2003, 21:1761-1769.
- Bangalore S, Shahane A, Parkar S, Messerli FH: Compliance and fixed-dose combination therapy. Curr Hypertens Rep 2007, 9:184-189.
- Lacourci─é┬¿re Y, Neutel JM, Davidai G, Koval S: A multicenter, 14- week study of telmisartan and ramipril in patients with mildto- moderate hypertension using ambulatory blood pressure monitoring. Am J Hypertens 2006, 19:104-112.
- Poirier L, de Champlain J, Larochelle P, Lamarre-Cliche M, Lacourciere Y: A comparison of the efficacy and duration of action of telmisartan, amlodipine and ramipril in patients with confirmed ambulatory hypertension. Blood Press Monit 2004, 9:231-236.
- Williams B, Gosse P, Lowe L, Harper R, on behalf of the PRISMA I Study Group: The prospective, randomized investigation of the safety and efficacy of telmisartan versus ramipril using ambulatory blood pressure monitoring (PRISMA I). J Hypertens 2006, 24:193-200.
- Lacourci─é┬¿re Y, Neutel JM, Schumacher H: Comparison of fixeddose combinations of telmisartan/hydrochlorothiazide 40/ 12.5 mg and 80/12.5 mg and a fixed-dose combination of losartan/hydrochlorothiazide 50/12.5 mg in mild to moderate essential hypertension: pooled analysis of two multicenter, prospective, randomized, open-label, blinded-end point (PROBE) trials. Clin Ther 2005, 27:1795-1805.
- Smith DH, Cramer MJ, Neutel JM, Hettiarachchi R, Koval S: Comparison of telmisartan versus losartan: meta-analysis of titration- to-response studies. Blood Press Monit 2003, 8:111-117.
- Neldam S, Edwards C, ATHOS Study Group: Telmisartan plus HCTZ vs. amlodipine plus HCTZ in older patients with systolic hypertension: results from a large ambulatory blood pressure monitoring study. Am J Geriatr Cardiol 2006, 15:151-160.
- Elliott HL, Meredith PA: Trough:peak ratio: clinically useful or practically irrelevant? J Hypertens 1995, 13:279-283.
- Stangier J, Su CAPF, Roth W: Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res 2000, 28:149-167.
- Lewington S, Clarke R, Qizilbash N, Peto R, Collins R: Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002, 360:1903-1913.
- Suzuki H, Kanno Y, Nakamoto H, Okada H, Sugahara S: Decline of renal function is associated with proteinuria and systolic blood pressure in the morning in diabetic nephropathy. Clin Exp Hypertens 2005, 27:129-138.
- Elliott WJ: Cyclic and circadian variations in cardiovascular events. Am J Hypertens 2001, 14:291S-295S.
- Sharma AM, Davidson JA, Gavin JR III, DeSousa NJ: Comparison of the antihypertensive efficacy of telmisartan/hydrochlorothiazide vs valsartan/hydrochlorothiazide in high-risk overweight/ obese patients with hypertension and type 2 diabetes. Hypertension 2005, 46:898-899.