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.