Journal of Clinical Pharmacy and Therapeutics (2011) 36, 103–110

doi:10.1111/j.1365-2710.2010.01161.x

ORIGINAL ARTICLE

Inhibition of intestinal cholesterol absorption might explain cholesterol-lowering effect of telmisartan T. Inoue* MD PhD , I. Taguchi* MD PhD , S. Abe* MD PhD , S. Toyoda* MD PhD , M. Sakuma MD and K. Node MD PhD *Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Tochigi and Department of Cardiovascular and Renal Medicine, Saga University, Saga, Japan SUMMARY

What is known and objective: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), acts as a partial agonist for peroxisome proliferatoractivated receptor-c, and thus improves abnormalities of glucose metabolism and hypertriglyceridaemia in addition to its documented blood pressure-lowering effects. Recently, it has been demonstrated that telmisartan also lowers the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. This study was designed to investigate the mechanism of cholesterol reduction. Methods: We measured serum levels of cholestanol, a cholesterol absorption marker, and lathosterol, a cholesterol synthesis marker, in 20 patients with both hypercholesterolaemia and hypertension. Ten patients were treated with telmisartan and the remaining 10 with fluvastatin. Results: After 3 months of treatment, total and LDL cholesterol levels decreased in the telmisartan group (P < 0Æ01 for both total and LDL cholesterol levels) and the fluvastatin group (P < 0Æ001 for both total and LDL cholesterol levels). The change in cholestanol level after 3 months of treatment was positively correlated with the levels of total (R = 0Æ72, P < 0Æ05) and LDL cholesterol (R = 0Æ81, P < 0Æ01) in the telmisartan group. The change in lathosterol level was positively correlated with the levels of total (R = 0Æ88, P = 0Æ001) and LDL cholesterol (R = 0Æ89, P = 0Æ001) in the fluvastatin group. Received 13 September 2009, Accepted 04 January 2010 Correspondence: Teruo Inoue, Department of Cardiovascular Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. Tel.: 81 282 87 2146; fax: 81 282 86 5633; e-mail: [email protected]

 2010 Blackwell Publishing Ltd

What is new and conclusions: Our results suggest that the cholesterol-lowering effect of telmisartan might be caused by inhibition of cholesterol absorption, whereas that of statins is by inhibition of cholesterol synthesis. If confirmed, co-treatment with the two agents may be useful for synergistically lowering cholesterol in hypertensive patients. Keywords: cholestanol, cholesterol, cholesterol absorption, low-density lipoprotein cholesterol, telmisartan

INTRODUCTION

Telmisartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), acts as a partial agonist of peroxisome proliferator-activated receptor (PPAR)-c, and thus is believed to have direct cardiovascular end-organ protection that goes beyond blood pressure control (1, 2). In addition to direct end-organ protection, telmisartan improves abnormalities of glucose and lipid metabolism, leading to a reduction in atherosclerosis. Telmisartan ameliorates insulin resistance and hypertriglyceridaemia and thereby improves metabolic syndrome (3–5). Moreover, several studies suggest that telmisartan also reduces total cholesterol and low-density lipoprotein (LDL)-cholesterol levels, although the mechanism has not been established. We previously observed that telmisartan treatment reduced total cholesterol and LDL cholesterol levels and demonstrated that telmisartan reduced total cholesterol levels even in patients receiving statins. These findings suggest that the cholesterollowering mechanism of telmisartan may be independent from that of statins, namely by 103

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inhibiting cholesterol synthesis in the liver (6). We hypothesized the mechanism to be inhibition of intestinal cholesterol absorption. This study was designed to test this hypothesis. METHODS

Study design We recruited 10 outpatients with hypertension and hypercholesterolaemia (defined as total cholesterol level ‡220 mg ⁄ dL and ⁄ or LDL cholesterol level ‡120 mg ⁄ dL) with or without statin treatment. Telmisartan (40 mg ⁄ day) was administered to all patients for 3 months according to the following: (1) new therapy in patients receiving no antihypertensive medications (n = 3); (2) additional therapy in combination with other anti-hypertensive drugs such as calcium channel blockers or b-blockers in patients with poorly controlled hypertension (n = 4) or (3) in exchange for other renin angiotensin system inhibitors such as angiotensin converting enzyme inhibitors (ACEIs) or ARBs (n = 3). We also selected 10 age- and sexmatched patients with hypercholesterolaemia and no history of statin or other lipid-lowering medication use. These patients received fluvastatin (20 mg ⁄ day) for 3 months and were assessed as control subjects. During the 3-month observation period, there was no change in use of anti-hypertensive drugs, lipid-lowering drugs, anti-diabetic drugs or other lipid metabolism altering drugs. The study design was approved by local institutional review board and written informed consent was given by each patient. Lipid profiles and glucose metabolism parameters Fasting venous blood samples were taken from both the telmisartan and fluvastatin groups. The levels of serum total cholesterol and triglyceride were measured using an enzymatic technique. High-density lipoprotein (HDL) cholesterol and LDL cholesterol levels were determined by the homogenous assay. Fasting blood glucose level was assayed using the glucose oxidase method. Serum insulin level was measured by radioimmuno assay. Glycosylated haemoglobin A1C (HbA1c) level was measured by high performance liquid chromatography.

Markers for cholesterol absorption and cholesterol synthesis Serum contents of lipids were measured by gas– liquid chromatography from non-saponifiable serum samples (7). Each run quantitated cholesterol and non-cholesterol sterols including cholestanol, a cholesterol absorption marker, and lathosterol, a cholesterol synthesis marker (8, 9). These were expressed as ratios to 100 mg of cholesterol. Data analysis The data were collected at baseline before treatment and again at 3 months post-treatment (shown as mean ± SD). After the normality of variable distribution was assessed with the Kolmogorov– Smirnov test with Lilliefors’ correlation, intra- and inter-group comparisons were analyzed with the use of paired and unpaired Student’s t-tests, respectively, for continuous variables. Correlations between two parameters were assessed using simple linear regression analysis (P < 0Æ05). RESULTS

Treatment groups were matched for factors such as age, gender, body size, renal function, disease complications (diabetes, coronary artery or cerebrovascular diseases), and baseline medications (calcium channel blockers, b-blockers, renin angiotensin system inhibitors). Baseline statins were found in four telmisartan-treated patients, but not in any fluvastatin-treated patients (Table 1). Baseline levels of systolic blood pressure, triglyceride, HDL cholesterol, fasting blood glucose, fasting plasma insulin and HbA1c were also similar between the two groups. Although baseline levels of total cholesterol and LDL cholesterol were similar in the two groups, the baseline cholestanol levels were higher in the telmisartan group compared with the fluvastatin group (P < 0Æ01). There was no difference in lathosterol levels between the two groups at baseline. Three months after treatment, systolic blood pressure (P < 0Æ01) and fasting plasma insulin level (P < 0Æ05) decreased in the telmisartan group, but did not change in the fluvastatin group. Triglyceride levels decreased in the fluvastatin group (P < 0Æ05) but not in the

 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 36, 103–110

Cholesterol-lowering effects of telmisartan Table 1. Baseline characteristics in telmisartan and fluvastatin groups Age (year) Gender (male ⁄ female) Height (cm) Weight (kg) Creatinine (mg ⁄ dL) Complications (n) Diabetes Coronary artery disease Cerebrovascular disease Baseline medications (n) Ca channel blocker b-Blocker ACEl ⁄ ARB (except for telmisartan) Statin (except for fluvastatin)

105

Telmisartan (n = 10)

Fluvastatin (n = 10)

P-value

68 ± 13 5⁄5 154 ± 11 59 ± 13 0Æ85 ± 0Æ30

68 ± 12 5⁄5 155 ± 10 60 ± 15 0Æ86 ± 0Æ17

0Æ898 1Æ000 0Æ868 0Æ811 0Æ877

2 (20%) 1 (10%) 1 (10%)

2 (20%) 1 (10%) 1 (10%)

1Æ000 1Æ000 1Æ000

4 1 3 4

6 (60%) 2 (20%) 6 (60%) 0 (0%)

0Æ371 0Æ531 0Æ177 0Æ135

(40%) (10%) (30%) (40%)

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.

telmisartan group (Table 2). Total cholesterol level decreased in both groups of telmisartan (226 ± 42 to 206 ± 51 mg ⁄ dL, P < 0Æ01) and fluvastatin (217 ± 37 to 182 ± 31 mg ⁄ dL, P < 0Æ001). LDL cholesterol level also decreased in both the telmisartan (148 ± 24 to 129 ± 26 mg ⁄ dL, P < 0Æ01) and fluvastatin (148 ± 25 to 115 ± 19 mg ⁄ dL, P < 0Æ001) (Table 2; Fig. 1a) groups. The serum levels of cholestanol showed a decreasing trend in the telmisartan group (226 ± 24 to 206 ± 51 lg ⁄ 100g of cholesterol, P = 0Æ085) but no change in the fluvastatin group. On the contrary, the serum lathosterol levels did not change in the telmisartan group but showed a decreasing trend in the fluvastatin group (204 ± 129 to 129 ± 63 lg ⁄ 100g of cholesterol, P = 0Æ085) (Table 2; Fig. 1b). The changes in both total cholesterol level and LDL cholesterol level were not correlated with baseline levels of cholestanol and lathosterol in the telmisartan group. In the fluvastatin group, the changes were not correlated with baseline cholestanol level. However, the changes in total cholesterol level (R = 0Æ81, P < 0Æ01) and LDL cholesterol level (R = 0Æ70, P < 0Æ05) were positively correlated with the baseline lathosterol level. The changes in total cholesterol level (R = 0Æ72, P < 0Æ05) and LDL cholesterol level (P = 0Æ81, P < 0Æ01) were positively correlated with the change in cholestanol but not with the change in lathosterol found in the telmisartan group (Fig. 2). In the fluvastatin group, the changes in

total cholesterol level (R = 0Æ88, P = 0Æ001) and LDL cholesterol level (R = 0Æ89, P = 0Æ001) were positively correlated with the changes in lathosterol level but not with the changes in cholestanol level (Fig. 3). DISCUSSION

In the present study, we demonstrated that telmisartan reduced the levels of total cholesterol and LDL cholesterol, similar to fluvastatin. Telmisartan decreased cholestanol, a cholesterol absorption marker, whereas fluvastatin decreased lathosterol, a cholesterol synthesis marker. In addition, the reduction of total cholesterol and LDL cholesterol levels by telmisartan was associated with the change in cholestanol levels, whereas the reduction by fluvastatin was associated with the change in lathosterol levels. These results suggest that telmisartan lowers the cholesterol level via inhibition of cholesterol absorption, whereas statins lower cholesterol by inhibition of cholesterol synthesis. Although our results suggest that telmisartan inhibits intestinal cholesterol absorption, it is not clear whether the cholesterol-lowering effects are caused by AT1 receptor blocking or PPAR-c activation. Most ARBs increase insulin sensitivity and decrease triglyceride levels therefore potentially improving metabolic syndrome. ARBs regulate multiple levels of the insulin signalling

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Table 2. Blood pressure and other parameters of lipid and glucose metabolism in telmisartan and fluvastatin groups Telmisartan (n = 10)

Fluvastatin (n = 10)

Systolic blood pressure (mmHg) Baseline 147 ± 23 138 ± 12 3M 132 ± 22*** 134 ± 13 Change 11 ± 19 4±7 Triglyceride (mg ⁄ dL) Baseline 110 ± 39 141 ± 40 3M 91 ± 18 110 ± 51** Change 19 ± 34 32 ± 37 HDL cholesterol (mg ⁄ dL) Baseline 69 ± 30 55 ± 25 3M 66 ± 20 53 ± 20 Change 3Æ7 ± 11Æ9 2Æ3 ± 17Æ8 Fasting blood glucose (mg ⁄ dL) Baseline 100 ± 12 103 ± 17 3M 99 ± 12 104 ± 14 Change 0Æ5 ± 7Æ8 )0Æ5 ± 8Æ2 Fasting plasma insulin (mU ⁄ mL) Baseline 9Æ36 ± 6Æ79 7Æ01 ± 4Æ25 3M 5Æ77 ± 4Æ54** 6Æ80 ± 3Æ93 Change 3Æ6 ± 4Æ9 0Æ2 ± 5Æ6 Hemoglobin A1C (%) Baseline 5Æ3 ± 0Æ3 5Æ4 ± 0Æ4 3M 5Æ2 ± 0Æ3 5Æ5 ± 0Æ2 Change 0Æ12 ± 0Æ20 )0Æ15 ± 0Æ26 Total cholesterol(mg ⁄ dL) Baseline 232 ± 24 217 ± 37 3M 204 ± 31*** 182 ± 31 Change 28 ± 23 34 ± 19 LDL cholesterol (mg ⁄ dL) Baseline 148 ± 24 148 ± 25 3M 129 ± 26*** 115 ± 19 Change 19 ± 17 33 ± 19 Cholestanol (lg ⁄ 100 mg of cholesterol) Baseline 226 ± 42 176 ± 43 3M 206 ± 51* 159 ± 42 Change 20 ± 33 17 ± 39 Lathosterol (lg ⁄ 100 mg of cholesterol) Baseline 182 ± 104 204 ± 129 3M 167 ± 68 129 ± 63* Change 15 ± 60 75 ± 118

P-value

0Æ329 0Æ789 0Æ411 0Æ091 0Æ284 0Æ456 0Æ261 0Æ146 0Æ839 0Æ763 0Æ327 0Æ353 0Æ366 0Æ592 0Æ162 0Æ611 0Æ007 0Æ017 0Æ299 0Æ140 0Æ490 0Æ971 0Æ173 0Æ096 0Æ017 0Æ036 0Æ153 0Æ680 0Æ214 0Æ169

Changes were expressed by baseline values minus values at 3 months after the therapy. M, month; HDL, high-density lipoprotein; LDL, low-density lipoprotein. *P < 0Æ1, **P < 0Æ05, ***P < 0Æ01, P < 0Æ001 vs. baseline.

cascade such as the insulin receptor, insulin receptor substrate (IRS) and phosphatidylinositol 3 (PI3)-kinase by blocking the angiotensin 1 receptor (10–12), possibly leading to beneficial effects for the metabolic syndrome. Thus, the beneficial effect of telmisartan on glucose metabolism and hypertriglyceridaemia may be due to the effect as ARB and PPAR-c activation. Although several ARBs have been tested in clinical trials, telmisartan is the only ARB known to reduce total cholesterol or LDL cholesterol levels. Derosa et al. (13) performed a randomized study including 119 patients with mild hypertension and type 2 diabetes. They demonstrated that telmisartan (40 mg ⁄ day) treatment for 12 months produced significant reductions in total cholesterol and LDL cholesterol levels compared with placebo, whereas eprosartan (600 mg ⁄ day) did not significantly affect these parameters. Thus, the cholesterol-lowering effects are not considered a class effect of ARBs, but rather the specific action of telmisartan. We previously conducted a single-arm clinical trial, Saga Telmisartan Aggressive Research (STAR), that focused on the effect of telmisartan on lipid metabolism (6). A total of 197 patients with hypertension were prescribed 20–80 mg ⁄ day of telmisartan for 6 months. Overall, in addition to blood pressure reduction, telmisartan treatment achieved a 6% reduction in total cholesterol levels and a 9% reduction in LDL cholesterol levels. Surprisingly, an 18% reduction in total cholesterol levels was shown in a subset of patients with baseline levels ‡220 mg ⁄ dL. Interestingly, total cholesterol levels were reduced in patients receiving statins (12%). Thus, we speculated that the cholesterol-lowering mechanism of telmisartan might be different from that of statins which inhibit cholesterol synthesis in the liver. We hypothesized that telmisartan could inhibit cholesterol absorption in the intestine. Our hypothesis was tested by measuring the levels of cholestanol and lathosterol in patients with and without statin treatment. Intestinal cholesterol absorption was assessed using serum levels of cholestanol or plant sterols such as campesterol and sitosterol, whereas cholesterol synthesis was tested using serum levels of cholesterol precursors such as squalene, cholestenol, desmosterol and lathosterol (14). Patients with higher baseline cholestanol levels benefit less from statin

 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 36, 103–110

Cholesterol-lowering effects of telmisartan (a)

LDL cholesterol

Total cholesterol

mg/dL 300

107

mg/dL P = 0·004

P = 0·0003

220

P = 0·007

P = 0·0003

280 200 260 180

240

160

220 200

140

180 120 160 100

140 120

80 Baseline 3 Months Baseline 3 Months Telmisartan Fluvastatin (n = 10) (n = 10)

Baseline 3 Months Baseline 3 Months Telmisartan Fluvastatin (n = 10) (n = 10)

Fig. 1. (a) Changes in total cholesterol and LDL cholesterol levels after 3 months of treatment in both telmisartan and fluvastatin. Total cholesterol and LDL cholesterol levels decreased significantly in both telmisartan and fluvastatin treatment groups. (b) Changes in cholesterol and lathosterol levels after 3 months of telmisartan and fluvastatin treatment. Cholestanol levels decreased slightly in the telmisartan group but not in the fluvastatin group. On the contrary, lathosterol levels did not change in the telmisartan group but illustrated a slight decrease in the fluvastatin group.

(b)

C h o l es t a n o l

µg/100 mg of cholesterol P = 0·085 350

P = 0·200

Lathosterol µg/100 mg of cholesterol P = 0·450 500

P = 0·075

450 300 400 250

350 300

200 250 150

200 150

100 100 50

50 Baseline 3 Months Baseline 3 Months Telmisartan Fluvastatin (n = 10) (n = 10)

treatment (15), and more from cholesterol absorption inhibitors such as ezetimibe (16). In addition, baseline cholestanol levels are higher in patients who have received long-term statin treatment, compared with patients who have not (17). In our study, baseline cholestanol levels were higher in the telmisartan group, compared with the fluvastatin group. This is possibly related to the fact that 4 of the 10 patients in the telmisartan group had received statins prior to telmisartan administration. On the contrary, higher baseline lathosterol levels augment the effects of statins (18). In our study, the baseline lathosterol level was correlated with a reduction of total cholesterol and LDL cholesterol

Baseline 3 Months Baseline 3 Months Telmisartan Fluvastatin (n = 10) (n = 10)

levels in the fluvastatin group. Furthermore, the relationship between the change in lathosterol and that in total cholesterol and LDL cholesterol in the fluvastatin group is representative of the ability of statins to inhibit cholesterol synthesis. Although there was no correlation between baseline cholestanol level and cholesterol lowering in the telmisartan group, the relationship between the change in cholestanol levels and that in total cholesterol and LDL cholesterol levels suggest that telmisartan inhibits cholesterol by inhibiting intestinal absorption. The precise mechanism by which telmisartan decreases cholesterol absorption is still unknown.

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(a) Total cholesterol (mg/dL)

LDL cholesterol (mg/dL)

70 60

40

50

30

40 20

30 20

0 –10 –40

10

y = 50·2x + 17·7 R = 0·72 P = 0·017

10

–20

0

20

60

40

80

y = 42·7x + 10·6 R = 0·81 P = 0·005

0

100

–10 –40

–20

0

20

40

60

80

100

Cholestanol (µg/100 mg of cholesterol)

Cholestanol (µg/100 mg of cholesterol)

(b) LDL cholesterol (mg/dL) 80

Total cholesterol (mg/dL) 70

70

60

60

50

50 40 30 20

40 30

R = 0·17 P = 0·624

20 10

10 0 –80

–60

–40

–20

0

20

40

60

R = 0·11 P = 0·758

0 –80

100

–60

–40 –20 20 40 60 0 Cholestanol (µg/100 mg of cholesterol)

Cholestanol (µg/100 mg of cholesterol)

100

Fig. 2. (a) The relationship between the changes in total cholesterol and LDL cholesterol levels and the change in cholestanol levels after 3 months of telmisartan treatment. The changes in total cholesterol and LDL cholesterol levels were positively correlated with the change in cholestanol levels. (b) The relationship between the changes in total cholesterol and LDL cholesterol levels and the change in lathosterol level after 3 months of telmisartan treatment. The changes in total cholesterol and LDL cholesterol levels were not correlated with the change in lathosterol level.

(a) LDL cholesterol (mg/dL)

Total cholesterol (mg/dL) 70

40

60 50

30

40 20

30

R = 0·04 P = 0·915

20 10

0

0 –10 –100

R = 0·26 P = 0·468

10

50

0

–50

100

–10 –100

150

–50

50

0

100

150

Lathosterol (µg/100 mg of cholesterol)

Lathosterol (µg/100 mg of cholesterol)

(b) LDL cholesterol (mg/dL)

Total cholesterol (mg/dL)

80

70

70

60

60

50

50 40

40

30

y = 14·3x + 23·5 R = 0·88 P = 0·001

20

20

10 0 –100 –50

y = 14·0x + 22·7 R = 0·89 P = 0·001

30

10 0

50

100

150 200 250 300

Lathosterol (µg/100 mg of cholesterol)

350

0 –100 –50

0

50

100

150 200

250

300

Lathosterol (µg/100 mg of cholesterol)

Recently, it has been illustrated that adenosine triphosphate-binding cassette (ABC) transporters, ABCA1 and ABCG5 ⁄ G8, exist in enterocytes, and intestinal ABCs play an important role in intestinal cholesterol absorption (19, 20). The intestinal ABCs, ABCA1 (21) and ABCG5 ⁄ G8 (22), efflux free cholesterol from enterocytes back into the intestinal

350

Fig. 3. (a) The relationship between the changes in total cholesterol and LDL cholesterol levels and the change in cholestanol level after 3 months fluvastatin treatment. The changes in total cholesterol and LDL cholesterol levels were not correlated with the change in cholestanol level. (b) The relationship between the changes in total cholesterol and LDL cholesterol levels and the change in lathosterol level after 3 months of fluvastatin treatment. The changes in total cholesterol and LDL cholesterol levels were positively correlated with the change in lathosterol level.

lumen, thereby modulating net cholesterol absorption and efficiency. Liver X receptor a (LXRa) plays a crucial role in the regulation of cholesterol efflux from enterocytes back into the intestinal lumen via ABCA1 and ABCG5 ⁄ G8 (23) PPAR-c up-regulates LXRa gene expression, and therefore may indirectly regulate ABCA1 and

 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 36, 103–110

Cholesterol-lowering effects of telmisartan

ABCG5 ⁄ G8 (21), resulting in inhibition of intestinal cholesterol absorption. Thus, one possible mechanism by which telmisartan inhibits cholesterol absorption may be due to its PPAR-c activating effect. However, thiazolidinedione PPAR-c activators, pioglitazone and rosiglitazone, which have been shown to increase insulin sensitivity and decrease triglyceride level (24), have not been shown to lower total cholesterol and LDL cholesterol levels. In contrast to ligands such as thiazoilidinediones that fully activate PPAR-c, telmisartan acts as only a partial agonist; its PPAR-c activating potency is weak in vivo. Therefore, weak but not strong activation of PPAR-c as a partial agonist may lead to the cholesterol-lowering effect of telmisartan. In addition, it has been also demonstrated that angiotensin II directly reduces ABCA1 expression in mouse peripheral macrophages and ABCA1 promoter activity of in vitro cultured mouse peritoneal macrophages (25), and thus, there may be a direct effect of ARB on ABCA1 regulation, independently of PPAR-c. POTENTIAL LIMITATION ⁄ CLINICAL IMPLICATION

This study is a small non-randomized study. In this study, we assessed intestinal cholesterol absorption only by a measurement of the serum cholestanol as a cholesterol absorption marker, but not by direct measurement of absorption rate of radio-labelled cholesterol. Although the precise mechanisms are still speculative, this study suggests that the inhibition of intestinal cholesterol absorption is a possible mechanism for the observed cholesterollowering effect of telmisartan. To establish the clinical significance of the cholesterol-lowering effects of telmisartan, large-scale controlled clinical trials targeting cholesterol lowering as a primary endpoint and experimental studies to elucidate the mechanism would be required. What is new and conclusion Our results suggest that telmisartan lowers cholesterol probably through inhibition of absorption. Therefore, co-treatment with telmisartan and a statin may be a sound strategy for synergistically lowering cholesterol in patients with hypertension and dyslipidaemia.

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