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Telmisartan reduced abdominal circumference and body weight with decreasing triglyceride level in patients with type 2 diabetes and metabolic syndrome
Obesity Research & Clinical Practice (2010) 4, e145—e152
SHORT COMMUNICATION
Telmisartan reduced abdominal circumference and body weight with decreasing triglyceride level in patients with type 2 diabetes and metabolic syndrome Tetsuya Kakuma a,∗, Koro Gotoh a,b,c, Takayuki Masaki a, Emi Itateyama d, Nobuyuki Abe e, Hironobu Yoshimatsu a a
Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan b Ogata General Hospital, Oita, Japan c Okamoto Hospital, Oita, Japan d Usuki Cosmos Hospital, Oita, Japan e Naika Abe Clinic, Oita, Japan Received 5 June 2009 ; received in revised form 10 December 2009; accepted 16 December 2009
KEYWORDS Type 2 diabetes; Metabolic syndrome; Telmisartan; Abdominal circumference; Triglycerides
∗
Summary Telmisartan has the dual ability to inhibit angiotensin II type 1 receptors and activate peroxisome proliferator-activated receptor gamma (PPAR), especially as a selective PPAR modulator that does not strongly promote adipogenesis for weight gain. Accordingly, Telmisartan is expected to provide beneficial effects for glucose and lipid metabolism without causing obesity. In the present study, we examined the effects of Telmisartan in patients with type 2 diabetes and metabolic syndrome. Thirty-two patients enrolled in this study were administered 40 mg per day of Telmisartan for 6 months. Telmisartan treatment significantly reduced systolic and diastolic blood pressure accompanied by induction of plasma renin activity (PRA) and reduction of serum aldosterone concentration and significantly decreased waist circumference, body mass index (BMI), and triglycerides (TG). In the 16 patients who did not take sulfonylurea, fasting plasma glucose (FPG) decreased and HbA1c significantly decreased from 3 months to 6 months. The results provide evidence that Telmisartan may improve glucose and lipid metabolism with the reduction in visceral fat mass in patients with type 2 diabetes and metabolic syndrome. © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +81 97 586 5793; fax: +81 97 549 4480. E-mail address: [email protected] (T. Kakuma).
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.12.003
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Introduction Several clinical trials have shown that angiotensin II type 1 receptor blockers (ARBs) can reduce the incidence of new-onset type 2 diabetes via the improvement of insulin resistance [1—3] and prevent cardiovascular events through the development of atherosclerosis by normalizing endothelial dysfunction [4,5]. Therefore, ARBs have currently been recognized as useful antihypertensive drugs for the treatment of metabolic syndrome, which is a cluster of mild cardiovascular risk factors, characterized by visceral fat obesity, elevated blood pressure, dyslipidemia, and impaired glucose tolerance. For all ARBs, Telmisartan has demonstrated the ability not only to inhibit angiotensin II type 1 receptor but also to activate peroxisome proliferator-activated receptor gamma (PPAR␥) and to provide beneficial effects for glucose and lipid metabolism [6]. On the other hand, because Telmisartan works as a selective PPAR␥ modulator, its effects on gene expression partially differ from those of full agonists, such as thiazolidinediones, which strongly promote adipogenesis and cause weight gain. Microassay and quantitative PCR analysis showed that stimulation of Telmisartan on the expression of genes involved in adipocytic lipid storage, for example, prostacyclin receptor and glycerol kinase, was much weaker than that of pioglitazone [7]. This finding suggests that Telmisartan-induced PPAR␥ activation is not associated with weight gain. Indeed, we observed that Telmisartan treatment decreased the weight of visceral adipose tissue without affecting food intake in diet-induced obese mice and increased the mRNA expression of uncoupling protein 1 in brown adipose tissue, accompanied by an increase in oxygen consumption [8]. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in diet-induced obese mice all improved with Telmisartan treatment. Furthermore, Telmisartan treatment increased adiponectin mRNA in visceral adipose tissue and reduced the serum level of resistin, which impairs insulin sensitivity. Our results proposed that Telmisartan may prevent the development of obesity and related metabolic disorders by altering the levels of various adipocytokines and increasing energy expenditure. Recent reports indicate that the visceral fat area (VSA), estimated by abdominal computed tomography scan, decreased in patients with metabolic syndrome after Telmisartan treatment, while the subcutaneous fat area (SFA) did not [9], and the percentage of any decrease in body weight from baseline was significantly enhanced in hypertensive patients with glucose intolerance after Telmisartan
T. Kakuma et al. treatment, compared with Candesartan treatment [10]. However, a significant reduction in the actual measurement of body weight and waist circumference has not been reported. In this study, we examined the effects of Telmisartan on metabolic parameters, plasma renin activity (PRA), serum aldosterone concentration, and adipocytokine level in patients with type 2 diabetes and metabolic syndrome. We also performed sub-analysis in the patients who switched to Telmisartan from other ARBs or ACE inhibitor and were not taking sulfonylurea.
Subjects and methods Patients Outpatients of either sex, aged ≥18 years, with metabolic syndrome were recruited at Oita University hospital and its group hospitals. Metabolic syndrome was diagnosed according to the Japanese definition and criterion for metabolic syndrome [11]. Because elevated blood pressure (office systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg) was obligatory for the present study, the criterion for metabolic syndrome was as follows. In addition to abdominal obesity (waist circumstance ≥85 cm in men or ≥90 cm in women), at least one of the following clinical conditions should be observed: (A) dyslipidemia: triglyceride ≥150 mg/dl and/or HDL-cholesterol <40 mg/dl, (B) impaired glucose tolerance: fasting plasma glucose ≥110 mg/dl. Patients who were treated with antidiabetic, antidyslipidemic, and antihypertensive drugs fulfilled the criteria. Patients were excluded if they had a history of diabetic ketoacidosis or coma; impaired liver or renal dysfunction (defined as plasma aminotransferase and/or creatinine level higher than the upper limit of normal for age and sex, cholestatic disorder); or unstable angina, myocardial infarction, or stroke within the preceding 6 months; or any severe disease (infectious disease, freshly repaired status, external injury) likely to interfere with this study. Women who were pregnant or of childbearing potential were also excluded. Patients who received insulin therapy, thiazolidinediones or spironolactone, or had previously experienced hyperreactivity to Telmisartan were also excluded.
Study protocol and measurements Telmisartan 40 mg was orally administered after breakfast once a day for 6 months. When
Telmisartan reduced abdominal circumference and body weight the other antihypertensive drug that interrupts the renin—angiotensin system, such as ARB or angiotensin-converting enzyme (ACE) inhibitor, was already taken, it was changed to Telmisartan. If blood pressure control was still inadequate at a dose of 40 mg per day, the dose was increased to 80 mg per day. Dosage of other medications was not changed, and other antihypertensive drugs or others affecting glucose metabolism were not administered during treatment with Telmisartan. All patients underwent an initial screening assessment that included a medical history, physical examination, and vital signs before starting the study. At baseline and after 3 or 6 months of treatment, the following parameters were measured: systolic blood pressure (SBP) and diastolic blood pressure (DBP), body weight, waist circumference, glucose parameters (fasting plasma glucose [FPG], fasting immunoreactive insulin [FIRI], HbA1c, homeostasis model assessment of insulin resistance [HOMA-IR]), and fasting lipid profiles (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], and remnant lipoprotein cholesterol [RLP-C]; TC, HDL-C, and TG levels were determined using enzymatic technique and RLP-C was measured enzymatically with immunosorptive method). PRA, aldosterone, high molecular weight (HMW) adiponectin, and tumor necrosis factor (TNF)-␣ were also measured at baseline and after 6 months of treatment. Body mass index (BMI) was calculated as the ratio of weight (kilogram) to height2 (meter2 ). Insulin resistance was assessed by HOMA-IR (FPG × FIRI/405), as described by Matthews et al. [12]. Low-density lipoprotein cholesterol [LDL-C] was estimated by the Friedewald formula (TC − HDL-C − TG/5) when TG levels were below 400 mg/dl [13]. Waist circumference was measured at the umbilical level in the late exhalation phase of the standing position [14]. Blood pressure was measured in the sitting position after at least 5 min of rest. The study protocol was approved by the ethical committee of Oita University hospital, and all participants gave informed consent.
Statistical analysis Values are expressed as mean ± SEM. Data were analyzed by Wilcoxon matched-pair signed-rank to determine significant differences between before and after treatment. Statistical significance was defined as P < 0.05. All calculations were performed with StatView software (version 5.0 for Macintosh, SAS Institute Inc., Cary, NC, USA).
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Results General characteristics The characteristics of patients who could be successfully followed up 6 months after Telmisartan treatment are shown in Table 1. Sixteen patients treated with oral hypoglycemic agents were taking sulfonylurea either alone or in combination with other antidiabetic drugs, such as biguanides or ␣-glycosidase inhibitors, and 7 patients took ␣-glycosidase inhibitors either alone or in combination with biguanides, and 1 patients took biguanide. Most patients had already received antihypertensive drugs, including calcium channel blockers, ␣-blockers, -blockers, ACE inhibitors, and other ARBs. Telmisartan was administered as follows: (1) new isolated prescription in 4 drug-naïve patients; (2) additional therapy in combination with calcium channel blockers (9 patients); or (3) replacement therapy from the other ARBs (Candesartan 4 mg: 3 patients, 8 mg: 4 patients, 12 mg: 1 patient, Losartan 50 mg: 4 patients, Valsartan 80 mg: 4 patients) or ACE inhibitors (Enalapril 5 mg: 1 patient, Imidapril 5 mg: 2 patients). In the replacement therapy, 10 patients were already treated with calcium channel blockers, and each patient was treated with ␣-blocker or -blocker or in combination with calcium channel blocker and ␣blocker. The daily dose of Telmisartan was 40 mg in all patients as a result because the dosage was not changed. No adverse effects were observed during the follow-up period.
Table 1
Patient characteristics.
Number of patients Age (years)
32 64.4 ± 1.9
Gender Men (%) Women (%)
21 (66%) 11 (34%)
Treatment of diabetes mellitus Diet/exercise only (%) Oral hypoglycemic agents (%)
8 (25%) 24 (75%)
Treatment of dyslipidemia Statins (%) Fibrates (%)
9 (28%) 2 (6%)
Treatment of hypertension with Telmisartan New isolated prescription (%) 4 (13%) Additional prescription (%) 9 (28%) Exchanged prescription (%) 19 (59%) Exchange from ACEI (%) 3 (9%) Exchange from other ARBs (%) 16 (50%) ACEI: ACE inhibitors. Data are shown as mean ± SEM (n = 32).
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Effects of Telmisartan on anthropometric and metabolic parameters Changes in physical findings and biochemical parameters during the 6 months of treatment are shown in Table 2. At the end of the 6-month treatment period, BMI significantly decreased (26.8 ± 0.6 to 26.5 ± 0.6 kg/m2 , P < 0.05), and the decrease in BMI between 3 months and 6 months was statistically significant (26.6 ± 0.6 to 26.5 ± 0.6 mmHg, P < 0.05). Waist circumference also significantly decreased at 3 months (93.2 ± 1.2 to 91.7 ± 1.2 cm, P < 0.05) after Telmisartan treatment and remained decreased to 6 months (93.2 ± 1.2 to 91.4 ± 1.2 cm, P < 0.005). During the observation period, systolic and diastolic blood pressure decreased significantly (147.8 ± 2.2 to 138.3 ± 2.3 mm Hg, P < 0.0005, 84.7 ± 2.3 to 75.8 ± 2.1 mmHg, P < 0.0005, respectively), and the decrease in circumference between 3 months and 6 months was statistically significant (145.2 ± 2.4 to 138.3 ± 2.3 mmHg, P < 0.005, 82.2 ± 2.0 to 75.8 ± 2.1 mmHg, P < 0.0005, respectively). All parameters of glucose and lipid metabolism, except for TG, did not change after Telmisartan treatment (Table 2). TG continuously decreased and the difference 6 months after treatment was significant (153.9 ± 15.7 to 125.7 ± 10.2 mg/dl, P < 0.05). RLP-C also reduced (6.6 ± 0.8 to 6.3 ± 0.7 Table 2
to 5.5 ± 0.5 mg/dl), however, the decrease was not statistically significant. Then, PRA increased significantly (2.9 ± 0.5 to 5.7 ± 1.6 ng/ml/h, P < 0.005), while serum aldosterone concentration also decreased significantly (99.8 ± 8.6 to 84.0 ± 7.2 pg/ml, P < 0.05). No significant change was observed in HMW adiponectin during the 6 months of treatment. TNF-␣ level was below the detection range from baseline; therefore, statistical analysis was not performed in this study. Sub-analysis in this study: (1) in the 19 patients who switched to Telmisartan from other ARBs or ACE inhibitors, systolic and diastolic blood pressure decreased significantly (148.1 ± 3.0 to 139.1 ± 3.0 mmHg, P < 0.005, 84.0 ± 3.0 to 75.5 ± 2.9 mmHg, P < 0.005, respectively), PRA increased (3.7 ± 0.8 to 7.3 ± 2.6 ng/ml/h, P < 0.05) and serum aldosterone concentration decreased (105.3 ± 11.6 to 79.0 ± 13.6 pg/ml, P < 0.05). (2) In the 16 patients who were not taking sulfonylurea, both waist circumference and BMI decreased significantly at 3 months (93.4 ± 2.0 to 91.1 ± 1.7 cm, P < 0.05, 26.8 ± 0.8 to 26.6 ± 0.8 kg/m2 , P < 0.05, respectively) after Telmisartan treatment and remained decreased to 6 months (93.4 ± 2.0 to 90.9 ± 1.8 cm, P < 0.005, 26.8 ± 0.8 to 26.5 ± 0.8 kg/m2 , P < 0.05 respectively). In this case, FPG was likely to decrease during the observation period, but the decrease
Effects of Telmisartan on physical findings and biochemical parameters.
BMI (kg/m2 ) Waist circumference (cm) SBP (mmHg) DBP (mmHg) FPG (mg/dl) FIRI (U/ml) HOMA-IR HbA1c (%) TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) RLP-C (mg/dl) PRA (ng/ml/hr) Aldosterone (pg/ml) HMW adiponectin (g/ml) TNF-␣ (pg/ml)
Baseline
3 months
26.8 ± 0.6 93.2 ± 1.2 147.8 ± 2.2 84.7 ± 2.3 140.2 ± 5.5 9.6 ± 1.3 3.3 ± 0.6 6.8 ± 0.2 194.7 ± 7.0 113.0 ± 4.7 51.7 ± 2.3 153.9 ± 15.7 6.6 ± 0.8 2.9 ± 0.5 99.8 ± 8.6 4.6 ± 0.8 n.d
26.6 91.7 145.2 82.2 137.3 8.9 3.0 7.0 196.6 117.8 52.6 141.1 6.3
± ± ± ± ± ± ± ± ± ± ± ± ±
0.6 1.2* 2.4 2.0 4.7 1.1 0.4 0.2 4.9 3.5 2.2 16.0 0.7
6 months 26.5 ± 0.6*,† 91.4 ± 1.2** 138.3 ± 2.3***,†† 75.8 ± 2.1***,††† 138.1 ± 4.3 9.8 ± 1.4 3.3 ± 0.5 6.9 ± 0.1 196.2 ± 5.0 117.2 ± 3.5 53.9 ± 2.6 125.7 ± 10.2* 5.5 ± 0.5 5.7 ± 1.6** 84.0 ± 7.2* 4.9 ± 0.7 n.d
Statistical analysis was performed using Wilcoxon matched-pair signed-rank test. Data are shown as mean ± SEM (n = 32). nd: not detectable. Statistical significance was defined as P < 0.05. * P < 0.05 vs. baseline. ** P < 0.005 vs. baseline. *** P < 0.0005 vs. baseline. † P < 0.05 vs. 3 months. †† P < 0.005 vs. 3 months. ††† P < 0.0005 vs. 3 months.
Telmisartan reduced abdominal circumference and body weight was not significant (138.6 ± 7.3 to 136.9 ± 6.1 to 132.3 ± 5.7 mg/dl), and HbA1c decreased significantly from 3 months to 6 months (6.7 ± 0.2 to 6.4 ± 0.2 mmHg, P < 0.05).
Discussion The main findings of the present study are as follows: (1) Telmisartan significantly reduced systolic and diastolic blood pressure accompanied with induction of PRA and reduction of serum aldosterone concentration; (2) Telmisartan significantly decreased abdominal circumference, body weight, and TG. First, the reduction in both systolic and diastolic blood pressure was significant after 6 months of Telmisartan treatment, regardless of additional therapy or replacement with Telmisartan from other ARBs. It is reported that Telmisartan 80 mg significantly reduced 24-h mean systolic blood pressure (P < 0.05) and diastolic blood pressure (P < 0.05) compared with Losartan 50 mg [15]. In Japanese reports, Telmisartan has been shown to decrease blood pressure more than other ARBs [16—18]. To confirm this in our study, we explored the change in blood pressure only in the 19 patients who switched to Telmisartan from other ARBs or ACE inhibitors. The reduction in both systolic and diastolic blood pressure was significant, along with a significant induction of PRA and reduction in serum aldosterone concentration. The daily dose of Telmisartan was 40 mg in all patients as a result because the dosage was not changed. The titer was almost comparable with other ARBs that were used before switching. Our results support the previous experimental and clinical studies that Telmisartan is a more potent AT1-receptor antagonist than other ARBs currently in use and effectively inhibits the renin—angiotensin—aldosterone system [19—21]. In addition to blocking angiotension II type 1 receptor, Telmisartan activates PPAR␥, which affects the expression of key enzymes that mediate the beneficial effects of glucose and lipid metabolism. Thus, Telmisartan may provide added value not only in the treatment of hypertension but also in the prevention of metabolic syndrome. In the present study, the parameters of glucose metabolism and insulin resistance, such as FPG, FIRI, HbA1c, and HOMA-IR, did not change at 6 months after Telmisartan treatment, and HMW adiponectin level was not altered either. Although patients who received insulin therapy or thiazolidinediones were already excluded, some patients in this study were receiving sulfonylurea, which affected plasma insulin levels. Therefore, we com-
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pared the same parameters before and after Telmisartan treatment only in the 16 patients who were not receiving such treatment. FPG tended to decrease during the observation period, and HbA1c dropped significantly from 3 months to 6 months, indicating that glycemic control improved as described in previous reports [15,17,22]. The effect of Telmisartan on lipid metabolism has been reported. Derosa et al. first demonstrated that Telmisartan treatment for one year significantly improved lipid metabolism in hypertensive patients with type 2 diabetes mellitus, compared to eprosartan [23] and nifedipine [24]. Other groups also reported that Telmisartan was associated with a significant improvement in plasma TC and LDL-C concentration [17,25]. In the present study, Telmisartan reduced TG levels more, even in diabetic patients who were treated with biguanides (25%) and/or antidyslipidemic drugs, such as statins (28%) or fibrates (6%). Miura et al. [26] reported that 3-month Telmisartan treatment in exchange for Valsartan or Candesartan resulted in a significant decrease in TG as well as FIRI. Mori et al. [27] also demonstrated that switching therapy to Telmisartan from Candesartan significantly decreased TG levels and increased adiponectin levels. Usui et al. [28] showed that additional or exchanged treatment of Telmisartan from other ARBs significantly reduced FFA, but not TG. These three reports and our study fulfill all of the following characteristics of patients: (1) moderate type 2 diabetic mellitus patients (HbA1c: 6.9%, FPG: 130—150 mg/dl at baseline, antidiabetic therapy: more than 60%); (2) mildly obese patients (BMI: 26—27 kg/m2 ); and (3) replacement therapy to Telmisartan 40 mg from other ARBs or ACEI for 6 months (except for Usui el al. reports: 3 months). Furthermore, the advantage of Telmisartan on TG metabolism was not associated with the grade of dyslipidemia and the existence of antidyslipidemic agents. These findings suggest that Telmisartan may improve in an effective and efficient manner on hypertriglycemia, if we preferentially use it in middle stage diabetic patients with metabolic syndrome. In the present study, abdominal circumference and body weight decreased significantly after 6 months of Telmisartan treatment. This is the most exciting outcome that we expected on the basis of animal experiments [8] and must confirm in a clinical study. Although waist circumference was measured at the umbilical level in the late exhalation phase in a standing position [14], it may be difficult to assess credibility because the measurements of waist circumference differed at the measurer’s discretion. However, in the present study, the reduction in waist circumference syn-
e150 chronized to the reduction in body weight even in a multi-center trial. Unofficially, we asked to check all items at 12 months after Telmisartan treatment once again in patients who had not changed drugs. In 21 patients who gave permission, waist circumference remained decreased to 12 months, accompanying by a reduction in blood pressure, TG, and RLP-C (data not shown). These findings showed that Telmisartan reduced waist circumference and has maintained the effects for at least 12 months in 21 patients who did not pay attention to our study after the trial. Several reports support our results that Telmisartan has the ability to reduce adiposity in humans. Shimabukuro et al. [9] showed a trend for decreased body weight (76 ± 16 to 72 ± 12 kg, basal to 6 months, n = 27) and waist circumference (98 ± 11 to 93 ± 9 cm) without reaching statistical significance, consistent with the report of Usui et al. [28] (body weight; 92.0 ± 10.4 to 89.9 ± 8.9 cm, basal to 6 months, n = 36, waist circumference; 66.2 ± 12.8 to 66.0 ± 12.7 kg). In particular, it is noteworthy that the visceral fat area, determined by abdominal computed tomography scan, decreased after 6 months of Telmisartan treatment compared to baseline values [9]. Recently, Makita et al. [10] reported that the percentage of decrease in body weight from baseline significantly enhanced in hypertensive patients with glucose intolerance treated with Telmisartan for 6 months compared to the control group with no change in antihypertensive drugs. However, to our knowledge, the present study is the first report where absolute values of body weight and waist circumference significantly decreased after Telmisartan treatment. Sugimoto et al. showed that Telmisartan significantly attenuates weight gain in rats fed a high-fat, high-carbohydrate diet by increasing caloric expenditures [29], consistent with our previous report [8]. Moreover, the same group demonstrated that Telmisartan reduced the accumulation of visceral fat accompanied by decreasing adipocyte size to a much greater extent than Valsartan, similar to the report of Mori et al. [30]. On the other hand, Olmesartan has also been reported to downsize adipocytes in fructose-fed rats [31]. In fact, downsizing adipocytes per se via blocking type 1 angiotensin II receptor may be related, at least in part, to the reduction in body weight and waist circumference after Telmisartan treatment, but not only that, other mechanisms should account for the specificity of Telmisartan on adiposity. Telmisartan has also been known to activate PPAR␥. Okuno et al. [32] demonstrated that troglitazone, a full agonist of PPAR␥, increased the number of small adipocytes through the differentiation of preadipocytes and decreased the differentiated large adipocytes by
T. Kakuma et al. apoptosis in visceral fat tissue. This PPAR␥-induced fat remodeling leads to a decrease in visceral fat tissue instead of increasing subcutaneous fat tissue. However, Telmisartan does not work as a full PPAR␥ agonist but works as a selective PPAR␥ modulator characterized by the reduction in the effects that cause weight gain [7], indicating that Telmisartan can avoid the maximal side effects of a full PPAR␥ agonist. Taken together, the ability of Telmisartan to both work as a selective PPAR␥ modulator and to block the angiotensin II receptor goes forward to downsize the differentiated visceral adipocytes in a coordinated manner and may provide a reduction in body weight and waist circumference in human. In addition, another reason for the reduction in body weight and waist circumference in our study, unlike previous studies using Telmisartan, is explained below. At Oita university hospital or its group hospital, we emphasize to weight control rather than glycemic control on clinical examination of obese type 2 diabetes patient with metabolic syndrome. We often use the daily weight chart where obese patients should plot their body weight four times daily [33]. Charting daily weight has a useful role in long-time weight maintenance because patients are supposed to correct irregular lifestyle such as eating at night through the monitoring of their daily changes in body weight. Although we did not purposely introduce this method after Telmisartan treatment, our common practice might consequently avoid the cycle of weight loss and weight gain. Thus, the basal approach for obese patients may maximize the beneficial effect of Telmisartan in our study. Long-term weight maintenance per se must be most important for reducing the efficacy of Telmisartan on adiposity. This study and several recent reports provide evidence that Telmisartan improves glucose and lipid metabolism without weight gain. In addition, we propose that Telmisartan may reduce body weight and waist circumference in patients with type 2 diabetes and metabolic syndrome, if they always pay attention to avoiding weight gain. Furthermore, favorable effects tend to be expected, especially in men. Taken together, Telmisartan is a useful drug for metabolic syndrome, and it is most important to control body weight to maximize the beneficial effects of Telmisartan.
Study limitation There are some limitations to this study. We did not compare other ARBs and other antihypertensive drugs as control treatment; therefore, we cannot
Telmisartan reduced abdominal circumference and body weight completely demonstrate the specificity of Telmisartan. Fundamentally, this study only included a limited number of patients; larger scale studies will be required.
Conflict of interest
[12]
[13]
There is no conflict of interest. [14]
Acknowledgment
[15]
This work was supported by Astellas Pharma Inc. [16]
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[31] Furuhashi M, Ura N, Takizawa H, Yoshida D, Moniwa N, Murakami H, et al. Blockade of the renin—angiotensin system decreases adipocyte size with improvement in insulin sensitivity. J Hypertens 2004;22:1977—82. [32] Okuno A, Tamemoto H, Tobe K, Ueki K, Mori Y, Iwamoto K, et al. T Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998;101: 1354—61. [33] Fujimoto K, Sakata T, Etou H, Fukagawa K, Ookuma K, Terada K, et al. Charting of daily weight pattern reinforces maintenance of weight reduction in moderately obese patients. Am J Med Sci 1992;303:145—50.
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SHORT COMMUNICATION
Telmisartan reduced abdominal circumference and body weight with decreasing triglyceride level in patients with type 2 diabetes and metabolic syndrome Tetsuya Kakuma a,∗, Koro Gotoh a,b,c, Takayuki Masaki a, Emi Itateyama d, Nobuyuki Abe e, Hironobu Yoshimatsu a a
Department of Internal Medicine 1, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Oita 879-5593, Japan b Ogata General Hospital, Oita, Japan c Okamoto Hospital, Oita, Japan d Usuki Cosmos Hospital, Oita, Japan e Naika Abe Clinic, Oita, Japan Received 5 June 2009 ; received in revised form 10 December 2009; accepted 16 December 2009
KEYWORDS Type 2 diabetes; Metabolic syndrome; Telmisartan; Abdominal circumference; Triglycerides
∗
Summary Telmisartan has the dual ability to inhibit angiotensin II type 1 receptors and activate peroxisome proliferator-activated receptor gamma (PPAR), especially as a selective PPAR modulator that does not strongly promote adipogenesis for weight gain. Accordingly, Telmisartan is expected to provide beneficial effects for glucose and lipid metabolism without causing obesity. In the present study, we examined the effects of Telmisartan in patients with type 2 diabetes and metabolic syndrome. Thirty-two patients enrolled in this study were administered 40 mg per day of Telmisartan for 6 months. Telmisartan treatment significantly reduced systolic and diastolic blood pressure accompanied by induction of plasma renin activity (PRA) and reduction of serum aldosterone concentration and significantly decreased waist circumference, body mass index (BMI), and triglycerides (TG). In the 16 patients who did not take sulfonylurea, fasting plasma glucose (FPG) decreased and HbA1c significantly decreased from 3 months to 6 months. The results provide evidence that Telmisartan may improve glucose and lipid metabolism with the reduction in visceral fat mass in patients with type 2 diabetes and metabolic syndrome. © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Corresponding author. Tel.: +81 97 586 5793; fax: +81 97 549 4480. E-mail address: [email protected] (T. Kakuma).
1871-403X/$ — see front matter © 2009 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2009.12.003
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Introduction Several clinical trials have shown that angiotensin II type 1 receptor blockers (ARBs) can reduce the incidence of new-onset type 2 diabetes via the improvement of insulin resistance [1—3] and prevent cardiovascular events through the development of atherosclerosis by normalizing endothelial dysfunction [4,5]. Therefore, ARBs have currently been recognized as useful antihypertensive drugs for the treatment of metabolic syndrome, which is a cluster of mild cardiovascular risk factors, characterized by visceral fat obesity, elevated blood pressure, dyslipidemia, and impaired glucose tolerance. For all ARBs, Telmisartan has demonstrated the ability not only to inhibit angiotensin II type 1 receptor but also to activate peroxisome proliferator-activated receptor gamma (PPAR␥) and to provide beneficial effects for glucose and lipid metabolism [6]. On the other hand, because Telmisartan works as a selective PPAR␥ modulator, its effects on gene expression partially differ from those of full agonists, such as thiazolidinediones, which strongly promote adipogenesis and cause weight gain. Microassay and quantitative PCR analysis showed that stimulation of Telmisartan on the expression of genes involved in adipocytic lipid storage, for example, prostacyclin receptor and glycerol kinase, was much weaker than that of pioglitazone [7]. This finding suggests that Telmisartan-induced PPAR␥ activation is not associated with weight gain. Indeed, we observed that Telmisartan treatment decreased the weight of visceral adipose tissue without affecting food intake in diet-induced obese mice and increased the mRNA expression of uncoupling protein 1 in brown adipose tissue, accompanied by an increase in oxygen consumption [8]. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in diet-induced obese mice all improved with Telmisartan treatment. Furthermore, Telmisartan treatment increased adiponectin mRNA in visceral adipose tissue and reduced the serum level of resistin, which impairs insulin sensitivity. Our results proposed that Telmisartan may prevent the development of obesity and related metabolic disorders by altering the levels of various adipocytokines and increasing energy expenditure. Recent reports indicate that the visceral fat area (VSA), estimated by abdominal computed tomography scan, decreased in patients with metabolic syndrome after Telmisartan treatment, while the subcutaneous fat area (SFA) did not [9], and the percentage of any decrease in body weight from baseline was significantly enhanced in hypertensive patients with glucose intolerance after Telmisartan
T. Kakuma et al. treatment, compared with Candesartan treatment [10]. However, a significant reduction in the actual measurement of body weight and waist circumference has not been reported. In this study, we examined the effects of Telmisartan on metabolic parameters, plasma renin activity (PRA), serum aldosterone concentration, and adipocytokine level in patients with type 2 diabetes and metabolic syndrome. We also performed sub-analysis in the patients who switched to Telmisartan from other ARBs or ACE inhibitor and were not taking sulfonylurea.
Subjects and methods Patients Outpatients of either sex, aged ≥18 years, with metabolic syndrome were recruited at Oita University hospital and its group hospitals. Metabolic syndrome was diagnosed according to the Japanese definition and criterion for metabolic syndrome [11]. Because elevated blood pressure (office systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥85 mmHg) was obligatory for the present study, the criterion for metabolic syndrome was as follows. In addition to abdominal obesity (waist circumstance ≥85 cm in men or ≥90 cm in women), at least one of the following clinical conditions should be observed: (A) dyslipidemia: triglyceride ≥150 mg/dl and/or HDL-cholesterol <40 mg/dl, (B) impaired glucose tolerance: fasting plasma glucose ≥110 mg/dl. Patients who were treated with antidiabetic, antidyslipidemic, and antihypertensive drugs fulfilled the criteria. Patients were excluded if they had a history of diabetic ketoacidosis or coma; impaired liver or renal dysfunction (defined as plasma aminotransferase and/or creatinine level higher than the upper limit of normal for age and sex, cholestatic disorder); or unstable angina, myocardial infarction, or stroke within the preceding 6 months; or any severe disease (infectious disease, freshly repaired status, external injury) likely to interfere with this study. Women who were pregnant or of childbearing potential were also excluded. Patients who received insulin therapy, thiazolidinediones or spironolactone, or had previously experienced hyperreactivity to Telmisartan were also excluded.
Study protocol and measurements Telmisartan 40 mg was orally administered after breakfast once a day for 6 months. When
Telmisartan reduced abdominal circumference and body weight the other antihypertensive drug that interrupts the renin—angiotensin system, such as ARB or angiotensin-converting enzyme (ACE) inhibitor, was already taken, it was changed to Telmisartan. If blood pressure control was still inadequate at a dose of 40 mg per day, the dose was increased to 80 mg per day. Dosage of other medications was not changed, and other antihypertensive drugs or others affecting glucose metabolism were not administered during treatment with Telmisartan. All patients underwent an initial screening assessment that included a medical history, physical examination, and vital signs before starting the study. At baseline and after 3 or 6 months of treatment, the following parameters were measured: systolic blood pressure (SBP) and diastolic blood pressure (DBP), body weight, waist circumference, glucose parameters (fasting plasma glucose [FPG], fasting immunoreactive insulin [FIRI], HbA1c, homeostasis model assessment of insulin resistance [HOMA-IR]), and fasting lipid profiles (total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], and remnant lipoprotein cholesterol [RLP-C]; TC, HDL-C, and TG levels were determined using enzymatic technique and RLP-C was measured enzymatically with immunosorptive method). PRA, aldosterone, high molecular weight (HMW) adiponectin, and tumor necrosis factor (TNF)-␣ were also measured at baseline and after 6 months of treatment. Body mass index (BMI) was calculated as the ratio of weight (kilogram) to height2 (meter2 ). Insulin resistance was assessed by HOMA-IR (FPG × FIRI/405), as described by Matthews et al. [12]. Low-density lipoprotein cholesterol [LDL-C] was estimated by the Friedewald formula (TC − HDL-C − TG/5) when TG levels were below 400 mg/dl [13]. Waist circumference was measured at the umbilical level in the late exhalation phase of the standing position [14]. Blood pressure was measured in the sitting position after at least 5 min of rest. The study protocol was approved by the ethical committee of Oita University hospital, and all participants gave informed consent.
Statistical analysis Values are expressed as mean ± SEM. Data were analyzed by Wilcoxon matched-pair signed-rank to determine significant differences between before and after treatment. Statistical significance was defined as P < 0.05. All calculations were performed with StatView software (version 5.0 for Macintosh, SAS Institute Inc., Cary, NC, USA).
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Results General characteristics The characteristics of patients who could be successfully followed up 6 months after Telmisartan treatment are shown in Table 1. Sixteen patients treated with oral hypoglycemic agents were taking sulfonylurea either alone or in combination with other antidiabetic drugs, such as biguanides or ␣-glycosidase inhibitors, and 7 patients took ␣-glycosidase inhibitors either alone or in combination with biguanides, and 1 patients took biguanide. Most patients had already received antihypertensive drugs, including calcium channel blockers, ␣-blockers, -blockers, ACE inhibitors, and other ARBs. Telmisartan was administered as follows: (1) new isolated prescription in 4 drug-naïve patients; (2) additional therapy in combination with calcium channel blockers (9 patients); or (3) replacement therapy from the other ARBs (Candesartan 4 mg: 3 patients, 8 mg: 4 patients, 12 mg: 1 patient, Losartan 50 mg: 4 patients, Valsartan 80 mg: 4 patients) or ACE inhibitors (Enalapril 5 mg: 1 patient, Imidapril 5 mg: 2 patients). In the replacement therapy, 10 patients were already treated with calcium channel blockers, and each patient was treated with ␣-blocker or -blocker or in combination with calcium channel blocker and ␣blocker. The daily dose of Telmisartan was 40 mg in all patients as a result because the dosage was not changed. No adverse effects were observed during the follow-up period.
Table 1
Patient characteristics.
Number of patients Age (years)
32 64.4 ± 1.9
Gender Men (%) Women (%)
21 (66%) 11 (34%)
Treatment of diabetes mellitus Diet/exercise only (%) Oral hypoglycemic agents (%)
8 (25%) 24 (75%)
Treatment of dyslipidemia Statins (%) Fibrates (%)
9 (28%) 2 (6%)
Treatment of hypertension with Telmisartan New isolated prescription (%) 4 (13%) Additional prescription (%) 9 (28%) Exchanged prescription (%) 19 (59%) Exchange from ACEI (%) 3 (9%) Exchange from other ARBs (%) 16 (50%) ACEI: ACE inhibitors. Data are shown as mean ± SEM (n = 32).
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Effects of Telmisartan on anthropometric and metabolic parameters Changes in physical findings and biochemical parameters during the 6 months of treatment are shown in Table 2. At the end of the 6-month treatment period, BMI significantly decreased (26.8 ± 0.6 to 26.5 ± 0.6 kg/m2 , P < 0.05), and the decrease in BMI between 3 months and 6 months was statistically significant (26.6 ± 0.6 to 26.5 ± 0.6 mmHg, P < 0.05). Waist circumference also significantly decreased at 3 months (93.2 ± 1.2 to 91.7 ± 1.2 cm, P < 0.05) after Telmisartan treatment and remained decreased to 6 months (93.2 ± 1.2 to 91.4 ± 1.2 cm, P < 0.005). During the observation period, systolic and diastolic blood pressure decreased significantly (147.8 ± 2.2 to 138.3 ± 2.3 mm Hg, P < 0.0005, 84.7 ± 2.3 to 75.8 ± 2.1 mmHg, P < 0.0005, respectively), and the decrease in circumference between 3 months and 6 months was statistically significant (145.2 ± 2.4 to 138.3 ± 2.3 mmHg, P < 0.005, 82.2 ± 2.0 to 75.8 ± 2.1 mmHg, P < 0.0005, respectively). All parameters of glucose and lipid metabolism, except for TG, did not change after Telmisartan treatment (Table 2). TG continuously decreased and the difference 6 months after treatment was significant (153.9 ± 15.7 to 125.7 ± 10.2 mg/dl, P < 0.05). RLP-C also reduced (6.6 ± 0.8 to 6.3 ± 0.7 Table 2
to 5.5 ± 0.5 mg/dl), however, the decrease was not statistically significant. Then, PRA increased significantly (2.9 ± 0.5 to 5.7 ± 1.6 ng/ml/h, P < 0.005), while serum aldosterone concentration also decreased significantly (99.8 ± 8.6 to 84.0 ± 7.2 pg/ml, P < 0.05). No significant change was observed in HMW adiponectin during the 6 months of treatment. TNF-␣ level was below the detection range from baseline; therefore, statistical analysis was not performed in this study. Sub-analysis in this study: (1) in the 19 patients who switched to Telmisartan from other ARBs or ACE inhibitors, systolic and diastolic blood pressure decreased significantly (148.1 ± 3.0 to 139.1 ± 3.0 mmHg, P < 0.005, 84.0 ± 3.0 to 75.5 ± 2.9 mmHg, P < 0.005, respectively), PRA increased (3.7 ± 0.8 to 7.3 ± 2.6 ng/ml/h, P < 0.05) and serum aldosterone concentration decreased (105.3 ± 11.6 to 79.0 ± 13.6 pg/ml, P < 0.05). (2) In the 16 patients who were not taking sulfonylurea, both waist circumference and BMI decreased significantly at 3 months (93.4 ± 2.0 to 91.1 ± 1.7 cm, P < 0.05, 26.8 ± 0.8 to 26.6 ± 0.8 kg/m2 , P < 0.05, respectively) after Telmisartan treatment and remained decreased to 6 months (93.4 ± 2.0 to 90.9 ± 1.8 cm, P < 0.005, 26.8 ± 0.8 to 26.5 ± 0.8 kg/m2 , P < 0.05 respectively). In this case, FPG was likely to decrease during the observation period, but the decrease
Effects of Telmisartan on physical findings and biochemical parameters.
BMI (kg/m2 ) Waist circumference (cm) SBP (mmHg) DBP (mmHg) FPG (mg/dl) FIRI (U/ml) HOMA-IR HbA1c (%) TC (mg/dl) LDL-C (mg/dl) HDL-C (mg/dl) TG (mg/dl) RLP-C (mg/dl) PRA (ng/ml/hr) Aldosterone (pg/ml) HMW adiponectin (g/ml) TNF-␣ (pg/ml)
Baseline
3 months
26.8 ± 0.6 93.2 ± 1.2 147.8 ± 2.2 84.7 ± 2.3 140.2 ± 5.5 9.6 ± 1.3 3.3 ± 0.6 6.8 ± 0.2 194.7 ± 7.0 113.0 ± 4.7 51.7 ± 2.3 153.9 ± 15.7 6.6 ± 0.8 2.9 ± 0.5 99.8 ± 8.6 4.6 ± 0.8 n.d
26.6 91.7 145.2 82.2 137.3 8.9 3.0 7.0 196.6 117.8 52.6 141.1 6.3
± ± ± ± ± ± ± ± ± ± ± ± ±
0.6 1.2* 2.4 2.0 4.7 1.1 0.4 0.2 4.9 3.5 2.2 16.0 0.7
6 months 26.5 ± 0.6*,† 91.4 ± 1.2** 138.3 ± 2.3***,†† 75.8 ± 2.1***,††† 138.1 ± 4.3 9.8 ± 1.4 3.3 ± 0.5 6.9 ± 0.1 196.2 ± 5.0 117.2 ± 3.5 53.9 ± 2.6 125.7 ± 10.2* 5.5 ± 0.5 5.7 ± 1.6** 84.0 ± 7.2* 4.9 ± 0.7 n.d
Statistical analysis was performed using Wilcoxon matched-pair signed-rank test. Data are shown as mean ± SEM (n = 32). nd: not detectable. Statistical significance was defined as P < 0.05. * P < 0.05 vs. baseline. ** P < 0.005 vs. baseline. *** P < 0.0005 vs. baseline. † P < 0.05 vs. 3 months. †† P < 0.005 vs. 3 months. ††† P < 0.0005 vs. 3 months.
Telmisartan reduced abdominal circumference and body weight was not significant (138.6 ± 7.3 to 136.9 ± 6.1 to 132.3 ± 5.7 mg/dl), and HbA1c decreased significantly from 3 months to 6 months (6.7 ± 0.2 to 6.4 ± 0.2 mmHg, P < 0.05).
Discussion The main findings of the present study are as follows: (1) Telmisartan significantly reduced systolic and diastolic blood pressure accompanied with induction of PRA and reduction of serum aldosterone concentration; (2) Telmisartan significantly decreased abdominal circumference, body weight, and TG. First, the reduction in both systolic and diastolic blood pressure was significant after 6 months of Telmisartan treatment, regardless of additional therapy or replacement with Telmisartan from other ARBs. It is reported that Telmisartan 80 mg significantly reduced 24-h mean systolic blood pressure (P < 0.05) and diastolic blood pressure (P < 0.05) compared with Losartan 50 mg [15]. In Japanese reports, Telmisartan has been shown to decrease blood pressure more than other ARBs [16—18]. To confirm this in our study, we explored the change in blood pressure only in the 19 patients who switched to Telmisartan from other ARBs or ACE inhibitors. The reduction in both systolic and diastolic blood pressure was significant, along with a significant induction of PRA and reduction in serum aldosterone concentration. The daily dose of Telmisartan was 40 mg in all patients as a result because the dosage was not changed. The titer was almost comparable with other ARBs that were used before switching. Our results support the previous experimental and clinical studies that Telmisartan is a more potent AT1-receptor antagonist than other ARBs currently in use and effectively inhibits the renin—angiotensin—aldosterone system [19—21]. In addition to blocking angiotension II type 1 receptor, Telmisartan activates PPAR␥, which affects the expression of key enzymes that mediate the beneficial effects of glucose and lipid metabolism. Thus, Telmisartan may provide added value not only in the treatment of hypertension but also in the prevention of metabolic syndrome. In the present study, the parameters of glucose metabolism and insulin resistance, such as FPG, FIRI, HbA1c, and HOMA-IR, did not change at 6 months after Telmisartan treatment, and HMW adiponectin level was not altered either. Although patients who received insulin therapy or thiazolidinediones were already excluded, some patients in this study were receiving sulfonylurea, which affected plasma insulin levels. Therefore, we com-
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pared the same parameters before and after Telmisartan treatment only in the 16 patients who were not receiving such treatment. FPG tended to decrease during the observation period, and HbA1c dropped significantly from 3 months to 6 months, indicating that glycemic control improved as described in previous reports [15,17,22]. The effect of Telmisartan on lipid metabolism has been reported. Derosa et al. first demonstrated that Telmisartan treatment for one year significantly improved lipid metabolism in hypertensive patients with type 2 diabetes mellitus, compared to eprosartan [23] and nifedipine [24]. Other groups also reported that Telmisartan was associated with a significant improvement in plasma TC and LDL-C concentration [17,25]. In the present study, Telmisartan reduced TG levels more, even in diabetic patients who were treated with biguanides (25%) and/or antidyslipidemic drugs, such as statins (28%) or fibrates (6%). Miura et al. [26] reported that 3-month Telmisartan treatment in exchange for Valsartan or Candesartan resulted in a significant decrease in TG as well as FIRI. Mori et al. [27] also demonstrated that switching therapy to Telmisartan from Candesartan significantly decreased TG levels and increased adiponectin levels. Usui et al. [28] showed that additional or exchanged treatment of Telmisartan from other ARBs significantly reduced FFA, but not TG. These three reports and our study fulfill all of the following characteristics of patients: (1) moderate type 2 diabetic mellitus patients (HbA1c: 6.9%, FPG: 130—150 mg/dl at baseline, antidiabetic therapy: more than 60%); (2) mildly obese patients (BMI: 26—27 kg/m2 ); and (3) replacement therapy to Telmisartan 40 mg from other ARBs or ACEI for 6 months (except for Usui el al. reports: 3 months). Furthermore, the advantage of Telmisartan on TG metabolism was not associated with the grade of dyslipidemia and the existence of antidyslipidemic agents. These findings suggest that Telmisartan may improve in an effective and efficient manner on hypertriglycemia, if we preferentially use it in middle stage diabetic patients with metabolic syndrome. In the present study, abdominal circumference and body weight decreased significantly after 6 months of Telmisartan treatment. This is the most exciting outcome that we expected on the basis of animal experiments [8] and must confirm in a clinical study. Although waist circumference was measured at the umbilical level in the late exhalation phase in a standing position [14], it may be difficult to assess credibility because the measurements of waist circumference differed at the measurer’s discretion. However, in the present study, the reduction in waist circumference syn-
e150 chronized to the reduction in body weight even in a multi-center trial. Unofficially, we asked to check all items at 12 months after Telmisartan treatment once again in patients who had not changed drugs. In 21 patients who gave permission, waist circumference remained decreased to 12 months, accompanying by a reduction in blood pressure, TG, and RLP-C (data not shown). These findings showed that Telmisartan reduced waist circumference and has maintained the effects for at least 12 months in 21 patients who did not pay attention to our study after the trial. Several reports support our results that Telmisartan has the ability to reduce adiposity in humans. Shimabukuro et al. [9] showed a trend for decreased body weight (76 ± 16 to 72 ± 12 kg, basal to 6 months, n = 27) and waist circumference (98 ± 11 to 93 ± 9 cm) without reaching statistical significance, consistent with the report of Usui et al. [28] (body weight; 92.0 ± 10.4 to 89.9 ± 8.9 cm, basal to 6 months, n = 36, waist circumference; 66.2 ± 12.8 to 66.0 ± 12.7 kg). In particular, it is noteworthy that the visceral fat area, determined by abdominal computed tomography scan, decreased after 6 months of Telmisartan treatment compared to baseline values [9]. Recently, Makita et al. [10] reported that the percentage of decrease in body weight from baseline significantly enhanced in hypertensive patients with glucose intolerance treated with Telmisartan for 6 months compared to the control group with no change in antihypertensive drugs. However, to our knowledge, the present study is the first report where absolute values of body weight and waist circumference significantly decreased after Telmisartan treatment. Sugimoto et al. showed that Telmisartan significantly attenuates weight gain in rats fed a high-fat, high-carbohydrate diet by increasing caloric expenditures [29], consistent with our previous report [8]. Moreover, the same group demonstrated that Telmisartan reduced the accumulation of visceral fat accompanied by decreasing adipocyte size to a much greater extent than Valsartan, similar to the report of Mori et al. [30]. On the other hand, Olmesartan has also been reported to downsize adipocytes in fructose-fed rats [31]. In fact, downsizing adipocytes per se via blocking type 1 angiotensin II receptor may be related, at least in part, to the reduction in body weight and waist circumference after Telmisartan treatment, but not only that, other mechanisms should account for the specificity of Telmisartan on adiposity. Telmisartan has also been known to activate PPAR␥. Okuno et al. [32] demonstrated that troglitazone, a full agonist of PPAR␥, increased the number of small adipocytes through the differentiation of preadipocytes and decreased the differentiated large adipocytes by
T. Kakuma et al. apoptosis in visceral fat tissue. This PPAR␥-induced fat remodeling leads to a decrease in visceral fat tissue instead of increasing subcutaneous fat tissue. However, Telmisartan does not work as a full PPAR␥ agonist but works as a selective PPAR␥ modulator characterized by the reduction in the effects that cause weight gain [7], indicating that Telmisartan can avoid the maximal side effects of a full PPAR␥ agonist. Taken together, the ability of Telmisartan to both work as a selective PPAR␥ modulator and to block the angiotensin II receptor goes forward to downsize the differentiated visceral adipocytes in a coordinated manner and may provide a reduction in body weight and waist circumference in human. In addition, another reason for the reduction in body weight and waist circumference in our study, unlike previous studies using Telmisartan, is explained below. At Oita university hospital or its group hospital, we emphasize to weight control rather than glycemic control on clinical examination of obese type 2 diabetes patient with metabolic syndrome. We often use the daily weight chart where obese patients should plot their body weight four times daily [33]. Charting daily weight has a useful role in long-time weight maintenance because patients are supposed to correct irregular lifestyle such as eating at night through the monitoring of their daily changes in body weight. Although we did not purposely introduce this method after Telmisartan treatment, our common practice might consequently avoid the cycle of weight loss and weight gain. Thus, the basal approach for obese patients may maximize the beneficial effect of Telmisartan in our study. Long-term weight maintenance per se must be most important for reducing the efficacy of Telmisartan on adiposity. This study and several recent reports provide evidence that Telmisartan improves glucose and lipid metabolism without weight gain. In addition, we propose that Telmisartan may reduce body weight and waist circumference in patients with type 2 diabetes and metabolic syndrome, if they always pay attention to avoiding weight gain. Furthermore, favorable effects tend to be expected, especially in men. Taken together, Telmisartan is a useful drug for metabolic syndrome, and it is most important to control body weight to maximize the beneficial effects of Telmisartan.
Study limitation There are some limitations to this study. We did not compare other ARBs and other antihypertensive drugs as control treatment; therefore, we cannot
Telmisartan reduced abdominal circumference and body weight completely demonstrate the specificity of Telmisartan. Fundamentally, this study only included a limited number of patients; larger scale studies will be required.
Conflict of interest
[12]
[13]
There is no conflict of interest. [14]
Acknowledgment
[15]
This work was supported by Astellas Pharma Inc. [16]
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