Effects of Telmisartan Compared with Eprosartan on Blood

457

Original Article

Effects of Telmisartan Compared with Eprosartan on Blood Pressure Control, Glucose Metabolism and Lipid Profile in Hypertensive, Type 2 Diabetic Patients: a Randomized, Double-Blind, Placebo-Controlled 12-Month Study

Giuseppe DEROSA, Pietro D. RAGONESI＊, Amedeo MUGELLINI, Leonardina CICCARELLI, and Roberto FOGARI

We evaluated the antihypertensive activity, glucose homeostasis and plasma lipid profile in patients with mild hypertension and type 2 diabetes mellitus treated by diet and exercise, and not in receipt of oral hyper- glycemics, following 12-month treatment with either telmisartan or eprosartan. In this double-blind, placebo- controlled trial, 119 patients with mild essential hypertension (diastolic blood pressure [DBP] 91Ð104 mmHg) and type 2 diabetes were divided into three groups and randomized to receive once-daily telmisartan 40 mg, eprosartan 600 mg, or placebo for 12 months. At enrollment, patients were advised on diet (1,400Ð1,600 kcal/day) and exercise (physical aerobics on a bicycle for at least 30 min on 4 days each week). Compared with baseline, a significant reduction ( p＜0.01) in seated trough systolic blood pressure (SBP) was detected after 12-month treatment with either telmisartan or eprosartan. Seated trough DBP was also reduced by telmisartan ( p＜0.01) and eprosartan ( p＜0.05); the antihypertensive effect of telmisartan was significantly superior ( p＜0.05). No change in body mass index or glucose metabolism was observed with either active treatment, or with placebo. Telmisartan, but not eprosartan, significantly improved plasma total cholesterol ( p＜0.01), low-density lipoprotein cholesterol ( p＜0.01) and triglycerides ( p＜0.05) compared with eprosar- tan. In conclusion, 12-month telmisartan treatment produced a significantly greater reduction in DBP than eprosartan and significantly improved plasma lipids. The improvement could be due to varying pharmaco- kinetic/pharmacodynamic properties of telmisartan compared with eprosartan, even if it is not clear about the relationship between angiotensin-II receptor blockade and 3-hydroxy-3-methylglutaryl-coenzyme A reduc- tase inhibition. (Hypertens Res 2004; 27: 457Ð464)

Key Words: type 2 diabetes mellitus, telmisartan, eprosartan, lipid profile, glucose metabolism

or stroke is almost doubled when the hypertensive patient Introduction has diabetes mellitus (2). The lowering of blood pressure markedly decreases the rate of cardiovascular events and re- The incidence of hypertension in the diabetic population is nal deterioration in these patients (3). 1.5–3 times higher than in non-diabetic age-matched indi- Diabetic patients exhibit a number of characteristic viduals (1). In addition, the risk of any cardiovascular event changes in plasma lipoproteins, including elevated triglyc-

From the Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy, and ＊ Diabetes Care Unit, San Carlo Hospital, Milan, Italy. Address for Reprints: Giuseppe Derosa, M.D., Ph.D., Department of Internal Medicine and Therapeutics, University of Pavia, P. le C. Golgi 2. 27100 Pavia, Italy. E-mail: [email protected] Received December 26, 2003; Accepted in revised form March 25, 2004. 458 Hypertens Res Vol. 27, No. 7 (2004) erides (TG) and reduced high-density lipoprotein cholesterol with either telmisartan or eprosartan. (HDL-C) levels, with total cholesterol (TC) commonly re- maining at or close to the normal range (4). Several classes Methods of antihypertensive drugs can alter lipid metabolism (5). Two classes of antihypertensive agents—angiotensin-con- Patients verting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs)—target the renin–angiotensin–aldosterone Patients with type 2 diabetes, according to the American system (RAAS) and control the action of angiotensin II, Diabetes Association criteria (23), were eligible for inclusion. which is responsible for elevated blood pressure and patho- All patients were required to have been diagnosed as being genesis in the cardiovascular system (6). Metabolic abnor- diabetic for at least 2 years. During this time, diabetes had malities that are frequently associated with hypertension, been treated exclusively by diet and exercise in accordance such as insulin resistance and lipid profile impairment, can with the American Association of Clinical Endocrinologists be improved by ACE inhibitors (7). In addition, ACE in- for intensive diabetes self-management guidelines (24); oral hibitors have been shown to have no adverse effects on hyperglycemics had not been prescribed. In addition, all pa- glycemia or lipid profile (8, 9) and may have special protec- tients had to display mild essential hypertension according to tive properties against vascular and renal toxic effects of the World Health Organization—International Society of metabolic abnormalities (10). Hypertension criteria (i.e., diastolic blood pressure [DBP] Compared with ACE inhibitors, the ARBs offer more 90–99 mmHg) on repeated measurements (25). Patients with complete blockade of the RAAS (11), specifically inhibiting secondary hypertension, malignant hypertension, unstable the actions of angiotensin II at the level of the angiotensin-II angina, myocardial infarction within the preceding 6 months, type 1 (AT1) receptor. The ARBs are well tolerated and do liver dysfunction or renal impairment, or contraindications not appear to cause cough, a side-effect relatively frequently for or already receiving ARBs or ACE inhibitors were ex- observed in patients treated with ACE inhibitors (12). Many cluded. Eligible patients were fully informed of the aim of patients find this dry, persistent cough unacceptable; thus, the study, and their written informed consent was obtained. the superior tolerability profile of the ARBs may translate into improved compliance compared with ACE inhibitors. Study Design There are, however, few clinical data on the action of ARBs on metabolic parameters (13–17). This 12-month, randomized, double-blind, placebo-con- Telmisartan is an ARB that is highly selective for the AT1 trolled trial was performed in accordance with the principles receptor (18). Unique pharmacological features of telmisar- of the Declaration of Helsinki and was approved by the local tan include a long duration of action, as a result of a long ter- Ethics Committee. It was conducted in the Department of In- minal elimination half-life of about 24 h (18). At the recom- ternal Medicine and Therapeutics, University of Pavia, mended once-daily doses of 40 and 80 mg, telmisartan has Pavia, Italy. demonstrated good antihypertensive efficacy in double-blind, At the time of enrollment, there was reinforcement of the randomized, placebo-controlled clinical trials in both men importance of diet (1,400–1,600 kcal/day: 54% carbohy- and women with mild-to-moderate hypertension (18). drates, 24% proteins, 22% lipids [6% saturated], 108 mg Eprosartan is the first non-biphenyl, non-tetrazole ARB to cholesterol and 35 g fiber) and patients were instructed to be used clinically (19). Unlike telmisartan, which has a high maintain the same diet throughout the study. Alcohol con- volume of distribution of about 500 l (18), that of eprosartan sumption was not permitted during the study, and patients is less than 13 l (20). Also, the terminal elimination half-life were not allowed to take any other drugs, including oral hy- of eprosartan following oral administration is only 5–7 h perglycaemics or hypocholemic agents, or vitamin and/or (20), and it has a short duration of action (21). Unlike other mineral supplements. Dietary intake was recorded in a diary, ARBs, eprosartan appears to inhibit prejunctional and post- which was reviewed by dieticians as part of the continued synaptic AT1 (22), but the clinical implications are unknown. life-style modification program. In addition, patients were re- In clinical trials, at the recommended dose of 600 mg once quired to perform exercise on a bicycle for a minimum of 30 daily, eprosartan has been shown to be as effective an antihy- min on 4 days each week as recommended by the American pertensive as enalapril or losartan (19); there has, however, Association of Clinical Endocrinologists for intensive dia- been no direct comparison of the antihypertensive efficacy of betes self-management (24). Exercise compliance was dis- eprosartan with that of telmisartan. Furthermore, there are no cussed with the patient at each clinic visit. data directly comparing ARBs in hypertensive patients with After an initial 4-week, placebo wash-out period, patients diabetes mellitus. were randomized to receive once-daily telmisartan 40 mg, In this double-blind, placebo-controlled study, we evaluat- eprosartan 600 mg, or placebo for 12 months. Patients were ed glucose homeostasis and plasma lipid profile in patients instructed to take their medication in the morning after with mild hypertension and type 2 diabetes mellitus con- breakfast, except on the days of clinic visits. On these occa- trolled by diet and exercise alone after 12-month treatment sions, the assigned drug was taken after blood pressure mea- Derosa et al: Telmisartan vs. Eprosartan in Diabetics 459 surements had been performed at the clinic. This was to en- aseph Insulin radioimmunoassay (Pharmacia, Uppsala, Swe- sure that trough blood pressures (i.e., at the end of the dosing den). HbA1c was measured by aminophenylboronic acid affini- interval) were recorded. ty chromatography (DIAMAT, Bio-Rad, Richmond, USA; At the end of the placebo wash-out phase (baseline) and normal values 4.2–6.2%), with intra- and interassay coeffi- after 6 and 12 months of randomized treatment, body mass cients of variation of <2% (27), and plasma insulin concentra- index (BMI; 12 months only), fasting plasma glucose (FPG), tions were assayed using a radioimmunoassay kit (CEA Sorin, glycosylated hemoglobin (HbA1c), fasting plasma insulin Saluggia, Italy). The HOMA-IR was calculated using the fol- (FPI), homeostasis model assessment of insulin resistance lowing formula as described by Matthews and coworkers (28): (HOMA-IR), seated trough systolic blood pressure (SBP), HOMA-IR = FPI ( µU/ml)×FPG (mmol/l)/22.5. seated trough DBP, and lipid profile (plasma TC, low-densi- ty lipoprotein cholesterol [LDL-C; 12 months only], HDL-C Statistical Analysis and TG concentrations) were evaluated. Patients were also assessed for evidence of macroangiography (by electrocar- Data analysis was performed by means of the SPSS statisti- diography and Doppler examination), microalbuminuria and cal software package for Windows (version 9.0; SPSS Inc., neuropathy (vibration perception threshold) during the base- Chicago, USA); results were expressed as the mean±SD. line visit. One-way analysis of variance (ANOVA) was used to com- Blood pressure was measured using a standard mercury pare baseline data. Change was calculated as the value ob- sphygmomanometer (Korotkoff I and V) with a cuff of ap- tained at the end of 12-month treatment minus the value ob- propriate size on the right arm. Measurements were always tained at baseline. ANOVA was also used to assess the sig- taken by the same investigator in the morning after the sub- nificance within and between groups. A one-sample Stu- ject had been seated and resting for 10 min in a quiet room dent’s t-test was used to compare values obtained before and and before the once-daily intake of the randomized medica- after treatment, and two-sample t-tests were used for be- tion. The average of three successive measurements obtained tween-group comparison. Values of p<0.05 were considered at 1-min intervals was recorded. Heart rate was monitored at significant. each clinical visit after the patient had been seated for at least 10 min. Results Adverse events, intercurrent diseases, and patient compli- ance to the dosing regimen (assessed by counting the number Patient Demographics of pills returned at the clinic visits) were monitored at 12- week intervals during the randomized, double-blind treat- Baseline characteristics of the 119 enrolled patients with ment phase. Safety monitoring included physical examina- long-standing type 2 diabetes mellitus controlled by an in- tion, vital signs assessment, weight and height measurement, tensive diabetes self-management scheme (24) randomized and laboratory tests. to double-blind treatment with telmisartan 40 mg, eprosartan 600 mg, or placebo for 12 months were comparable (Table 1). The patients were non-smokers, had adequate glycemic Laboratory Evaluations control (HbA1c<7.0%), were not taking hypocholesterolemic The patients entered the research unit between 8:00 and 9:00 drugs and did not have any evidence of macroangiopathy, AM, after a 12-h overnight fast. All samples collected were nephropathy (albumin excretion rate <30 mg/24 h, per- transported within 4 h to a central laboratory at the authors’ formed on overnight urine collections) or neuropathy. Hy- hospital. A total of 15 ml blood (3 ml for HbA1c, 2 ml for pertension was recently diagnosed in >40% of the patients, FPG, 5 ml for FPI and 5 ml for lipid profile) was collected. but the self-management scheme for 3–6 months had failed Plasma was obtained by centrifugation at 1,000 ×g for 25 to lower blood pressure sufficiently. The study participants min at 4¼C and was assayed for TC and TG using enzymatic who had received prior antihypertensive therapy (24 in the methods (TC, CHOD-PAP (colorimetric method); TG, TG telmisartan group, 26 in the eprosartan group, and 21 in the without free glycerol; HITACHI 737; Hitachi, Tokyo, placebo group) were taken off their medication for at least 4 Japan). Determination of HDL-C was performed after the weeks to avoid carry-over effects. Prior treatment consisted precipitation of 1,006 g/ml infranatant with dextran sulfate– predominantly of calcium channel blockers, β-blockers, anti- magnesium chloride (26). LDL-C was measured by subtract- adrenergic agents or diuretics; the nature of the medication ing the HDL-C value from the infranatant TC value. The in- did not differ between the treatment groups. terassay coefficients of variation were 2.7% for TC, 9.1% for HDL-C and 2.0% for TG. Plasma glucose was assayed by the Blood Pressure Control hexokinase/glucose-6-phosphate dehydrogenase method us- ing a COBAS Mira Plus autoanalyzer (Hoffmann-La Roche, After 6 months of treatment, both telmisartan and eprosartan Basel, Switzerland). The interassay coefficient of variation significantly ( p<0.05) reduced SBP compared with baseline for glucose was 3.0%. Insulin was determined using Phadi- (Table 2). There was also a significant ( p<0.05) decrease in 460 Hypertens Res Vol. 27, No. 7 (2004)

Table 1. Demographics and Baseline Characteristics (Mean±SD) of Hypertensive Patients with Type 2 Diabetes Mellitus Randomized to Treatment with Telmisartan 40 mg, Eprosartan 600 mg, or Placebo for 12 Months Telmisartan Eprosartan Placebo Males/females 22/18 20/19 20/20 Age (years) 54±455±353±5 Duration of diabetes (years) 05±2 05±3 05±3 Heart rate (beats/min) 74±676±575±6 SBP (mmHg) 143±50 144±50 143±40 DBP (mmHg) 92±391±492±4 BMI (kg/m2) 26.9±1.2 26.4±1.3 26.2±1.1 HbA1c (%) 06.4±0.2 06.3±0.3 06.3±0.3 FPG (mg/dl) 128±14 130±16 126±15 FPI ( µU/ml) 19.4±3.8 19.2±4.1 19.0±3.9 HOMA-IR 05.1±3.6 05.3±3.8 05.0±3.9 TC (mg/dl) 195±18 193±20 197±17 LDL-C (mg/dl) 130±19 125±22 129±18 HDL-C (mg/dl) 42±542±443±3 TG (mg/dl) 125±32 129±30 126±36

SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HOMA-IR, homeostasis assessment model of insulin resistance; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

Table 2. Effect of Telmisartan 40 mg, Eprosartan 600 mg and Placebo Administration for 6 and 12 Months on Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Telmisartan Eprosartan Placebo Baseline 6 months 12 months Baseline 6 months 12 months Baseline 6 months 12 months SBP (mmHg) 143±5 139±4＊,§ 135±4＊＊, ‡ 144±5 140±5＊,§ 137±5＊＊,‡ 143±4 142±4 141±4 DBP (mmHg) 092±3 087±4 084±3＊＊, ‡, † 091±4 089±5 087±5＊, † 092±4 091±5 090±4 ＊p<0.05 vs. baseline. ＊＊ p<0.01 vs. baseline. § p<0.01 vs. placebo at 6 months. ‡ p<0.01 vs. placebo at 12 months. † p<0.05 vs. placebo at 12 months.

DBP in telmisartan-treated patients compared with baseline. 12 months did not result in any changes in BMI, HbA1c, At the end of the 12-month double-blind treatment, both FPG, FPI, or HOMA-IR compared with baseline, and there telmisartan and eprosartan brought about a significant reduc- were no significant differences in any of these parameters for tion ( p<0.01) in seated trough SBP compared with baseline, patients receiving the active treatments compared with those whereas no significant reduction was observed in the placebo in the placebo group (Table 3). group. The mean±SD reductions in SBP were 8±2 mmHg for telmisartan and 7±2 mmHg for eprosartan. Significant Lipid Profile reductions in trough DBP compared with baseline were also noted with telmisartan ( p<0.01) and eprosartan ( p<0.05), After 6-month telmisartan treatment, there was a significant but not with placebo. The mean±SD reductions in SBP reduction in plasma TC (Table 4). At 12 months, telmisartan were 8±2 mmHg for telmisartan and 4±1 mmHg for treatment resulted in a significant reduction in plasma TC eprosartan. The post-treatment trough DBP was significantly ( p<0.01), LDL-C ( p<0.01) and TG ( p<0.05) compared lower ( p<0.05) in the telmisartan group compared with the with baseline. By contrast, there were no significant changes eprosartan group. No significant changes in heart rate com- compared with baseline in the lipid profile of patients who pared with baseline were observed in any of the treatment had received eprosartan or placebo for 12 months. The re- groups. ductions in lipid levels achieved with telmisartan were sig- nificantly greater ( p<0.05) than those by eprosartan. Glucose Metabolism Telmisartan, eprosartan, or placebo administration for 6 and Derosa et al: Telmisartan vs. Eprosartan in Diabetics 461

Table 3. Effect of Telmisartan 40 mg, Eprosartan 600 mg and Placebo Administration for 6 and 12 Months on Body Mass In- dex (BMI) and Glucose Metabolism in Hypertensive Patients with Type 2 Diabetes Mellitus

Telmisartan Eprosartan Placebo Baseline 6 months 12 months Baseline 6 months 12 months Baseline 6 months 12 months BMI (kg/m2) 26.9±1.2 26.7±1.1 26.5±1.0 26.4±1.3 036.3±1.2 26.2±1.2 26.2±1.1 26.4±1.1 26.3±1.2 HbA1c (%) 06.4±0.2 06.4±0.4 06.3±0.3 06.3±0.3 006.2±0.3 06.2±0.4 06.3±0.3 06.3±0.2 06.4±0.2 FPG (mg/dl) .128±14 .125±16 .123±15 .130±16 .0131±17 .128±7 .126±15 .127±15 .125±4 FPI (µU/ml) 19.4±3.8 19.3±4.0 19.1±3.9 19.2±4.1 191.1±3.9 19.0±4.0 19.0±3.9 19.1±4.0 19.1±4.1 HOMA-IR 05.1±3.6 05.0±3.6 04.9±3.5 05.3±3.8 005.2±3.7 05.1±3.6 05.0±3.9 05.0±3.8 04.9±3.7

HbA1c, glycosylated hemoglobin; FPG, fasting plasma glucose; FPI, fasting plasma insulin; HOMA-IR, homeostasis assessment model of insulin resistance.

Table 4. Effect of Telmisartan 40 mg, Eprosartan 600 mg and Placebo Administration for 6 and 12 Months on Serum Lipid Profile in Hypertensive Patients with Type 2 Diabetes Mellitus

Telmisartan Eprosartan Placebo Baseline 6 months 12 months Baseline 6 months 12 months Baseline 6 months 12 months TC (mg/dl) 195±18 186±19＊ 180±20＊＊, †, ‡ 193±20 192±21 190±19＊＊ 197±17 198±20 195±18 LDL-C (mg/dl) 130±1 122±17＊ 119±18＊＊, †, ‡ 125±22 127±19 124±20 129±18 129±19 127±21 HDL-C (mg/dl) 042±5 044±5 043±4＊＊, †, ‡ 042±4 040±5 041±5 043±3 043±4 042±4 TG (mg/dl) 125±32 112±31 094±30＊, †, ‡ 129±30 126±29 121±28 126±36 129±33 128±31 ＊p<0.05 vs. baseline. ＊＊p<0.01 vs. baseline. †p<0.05 vs. placebo at 12 months. ‡p<0.05 vs. eprosartan at 12 months. TC, total choles- terol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides.

fits of the required exercise and diet. Safety Nevertheless, pharmacological intervention may be neces- During the initial 4-week, placebo wash-out period, three pa- sary to control blood pressure and minimize cardiovascular tients experienced mild adverse events: fatigue in two pa- complications. The present study comprised patients who tients and headache in one patient. During the 12-month were mildly hypertensive. The importance of angiotensin II double-blind treatment period, five patients reported mild ad- in the pathophysiology of cardiovascular disease is well verse events: fatigue in one in the telmisartan group and one known (6), and there is evidence that overactivity of the in the placebo group, dizziness in two in the eprosartan RAAS may impair the intracellular response to insulin sig- group and headache in one in the placebo group. naling (29). The ACE inhibitors have been shown, in addi- Compared with placebo, no serious adverse effects oc- tion to providing effective blood pressure control, not to curred in patients in the telmisartan or eprosartan group. No have any negative effect on glycemia or insulin sensitivity event resulted in withdrawal from the study. (30). Recently, the relationship between cardiovascular dis- ease, the metabolic syndrome, diabetes and hypertension and γ Discussion the role of peroxisome proliferator-activated receptor- (PPARγ) has been demonstrated (31). Preliminary data sug- In patients with type 2 diabetes mellitus, the aim is to pre- gest that the ARB telmisartan increases PPARγ activity and vent the emergence of insulin resistance, maintain a favor- may provide additional benefits in the treatment of type 2 di- able lipid profile, and control hypertension in order to mini- abetes (32). mize cardiovascular complications and improve patient Clinical studies have indicated that, for ARBs, reductions prognosis. This may be achieved using an intensive system in blood pressure are comparable to those achieved with of diabetes self-management, with a diabetes management ACE inhibitors (33). In addition, the beneficial effects of a team including dieticians playing a critical role (24). The co- low dose of an ARB in the prevention of target organ dam- ordinated efforts of the team are reflected in the normaliza- age have been demonstrated in mildly hypertensive patients tion of the patients’ glycosylated hemoglobin and free plas- with type 2 diabetes, with prevention of early kidney damage ma glucose by intensive life-style modification in the pa- being independent of the antihypertensive activity (34). To tients at baseline, despite the patients having been diabetic date, the ARBs valsartan, losartan, and candesartan cilexetil for at least 2 years. This approach was continued during the given for periods of up to 12 weeks have been shown not to study, with regular counseling sessions to reinforce the bene- affect glucose homeostasis (16, 35, 36) and, when given for a 462 Hypertens Res Vol. 27, No. 7 (2004) period of 12 weeks, valsartan and candesartan cilexetil did group, after 1-year treatment, the SBP/DBP was 135± not adversely affect the lipid profile of diabetic patients with 4/84±3 mmHg using the lower recommended once-daily hypertension (16, 36). Only one study has evaluated the dose of 40 mg compared with values of 137±5/87±5 longer-term impact on lipid profiles in diabetic patients (17). mmHg for eprosartan 600 mg given once daily. Derosa et al., comparing the ACE inhibitor perindopril and The absence of changes in FPG, HbA1ac, FPI, or HOMA- the ARB candesartan cilexetil after 12-month administration, IR may be partly attributed to the continuation of a diet and found that only perindopril produced significant improve- exercise regime that the patients had followed since the diag- ments in metabolic parameters. nosis of diabetes at least 2 years before enrollment into this In the present study, at the end of the 12-month active study. Other studies have not necessarily adopted an inten- treatment, once-daily telmisartan provided significantly su- sive regime for the self-management of diabetes as recom- perior control of trough DBP compared with once-daily mended by the American Association of Clinical Endocri- eprosartan. However, there was no significant difference in nologists (24), and this may impact metabolic parameters. the reduction in SBP achieved with telmisartan or eprosar- The plasma lipid profile of diabetic patients is especially tan. It should be noted that the 40 mg dose was the lower of important given the high incidence of atherosclerosis in dia- the two telmisartan monotherapy doses recommended for the betic patients (41). In comparison with once-daily eprosartan treatment of hypertension. The recommended dose range for 600 mg, telmisartan treatment at a dose of 40 mg once daily eprosartan is 400–800 mg; the starting dose is usually resulted in a significant reduction in plasma LDL-C, TC, and 600 mg, with an increase to 800 mg if the response is insuffi- TG levels. With eprosartan, lipid levels were similar to those cient to achieve target blood pressure. In the present study, observed in placebo-treated patients maintained on a strict the ARB dose remained unaltered throughout the treatment diet with restricted fat intake. This distinction between period. telmisartan and eprosartan may possibly be explained by the The significantly greater reduction in trough (i.e., at the high lipophilicity of telmisartan compared with eprosartan end of the dosing interval) DBP with telmisartan compared and other ARBs (42) and the PPARγ-modulating effect of with eprosartan observed in this study may be attributed to telmisartan (34). Other structural differences among the the former’s long terminal elimination half-life compared ARBs may also contribute to the possible differences in with that of eprosartan (18, 20). The advantages of the metabolic profiles; however, other than this study there are longer action of telmisartan may extend to the prevention of currently no head-to-head comparisons of different antihy- cardiovascular events, which follow a similar circadian pat- pertensives of this class. tern, with an increase in their incidence being associated These results suggest that there are differences between with the early morning blood pressure surge (37). For a drug ARBs. Telmisartan, after administration for 12 months, con- with a short half-life taken in the morning, the time of maxi- ferred significant advantages compared with eprosartan in mal cardiovascular risk is likely to coincide with a period of terms of blood pressure control and plasma lipid levels in di- suboptimal blood pressure control. abetic patients with hypertension. No data are available on The comparable reduction in SBP in both the telmisartan the relationship between ARB and 3-hydroxy-3-methylglu- and eprosartan groups observed in the present study may be taryl-coenzyme A (HMG-CoA) reductase inhibition. It is explained by the SBP being related to sympathetic activity. possible that telmisartan, because of its long duration of Preclinical data suggest that eprosartan exerts sympathoin- action, may have additive effects on the inhibition of HMG- hibitory activity (38). In another study comparing eprosartan CoA reductase and other mechanisms controlling metabolic 400 mg twice daily with enalapril 10 mg once daily in the disorders. Further studies are required to assess such possi- treatment of severe hypertension, the effects of the two anti- bilities. hypertensive agents on DBP were comparable, whereas eprosartan brought about a significantly superior reduction of References SBP (39). The importance of aggressive blood pressure control in 1. 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