Journal of Human Hypertension (2006) 20, 860–866 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Improved sensitivity with the angiotensin II-receptor blocker losartan in patients with hypertension and other cardiovascular risk factors

TA Aksnes1, HM Reims2, S Guptha3, A Moan4,IOs5 and SE Kjeldsen6 1Department of Cardiology, Ullevaal University Hospital, Oslo, Norway; 2Department of Cardiology, Ullevaal University Hospital, Oslo, Norway; 3Merck & Co., Whitehouse Station, New Jersey, USA; 4MSD AS, Drammen, Norway; 5Department of Nephrology, Ullevaal University Hospital, Oslo, Norway and 6Department of Cardiology, Ullevaal University Hospital, Oslo, Norway

We aimed to compare the effects of two different a 4-week open-label wash-out phase, the participants vasodilating principles, angiotensin II-receptor blockade crossed over to the opposite treatment regimen and and calcium channel blockade, on peripheral insulin- final examinations with hyperinsulinaemic isoglycaemic mediated glucose uptake in patients with hypertension glucose clamp after another 8 weeks. Blood pressure and other cardiovascular risk factors. Twenty-one was lowered to the same level in both treatment periods. hypertensive patients (11 women and 10 men) with The glucose disposal rate was significantly higher after mean age 58.6 years (range 46–75 years), body mass treatment with losartan 100 mg þ amlodipine 5 mg com- index 29.271.0 kg/m2 and blood pressure 16073/ pared to amlodipine 10 mg (4.970.4 vs 4.270.5 mg/kg/ 9672 mm Hg entered a 4-week run-in period with min, P ¼ 0.039). Thus our data suggest that angiotensin open-label amlodipine 5 mg. Thereafter they were ran- II-receptor blockade with losartan improves glucose domized double-blindly to additional treatment with metabolism at the cellular level beyond what can be amlodipine 5 mg or losartan 100 mg. After 8 weeks of expected by the vasodilatation and blood pressure treatment, all patients underwent clinical examination reduction alone. and laboratory testing, and 17 of them underwent a Journal of Human Hypertension (2006) 20, 860–866. hyperinsulinaemic isoglycaemic glucose clamp. After doi:10.1038/sj.jhh.1002087; published online 21 September 2006

Keywords: angiotensin II type I receptor blockers; calcium channel blockers; mellitus; hypertension;

Introduction angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II-receptor blockers (ARBs) and calcium Patients with hypertension have an increased pre- channel blockers (CCBs).4–6 Furthermore, the Val- valence of insulin resistance and an increased risk 1 sartan Antihypertensive Long-Term Use Evaluation of developing diabetes mellitus with ageing. As (VALUE) trial7 recently observed a 23% reduction in high blood pressure is encountered in more than 2 development of type II diabetes mellitus with ARB- 20% of the adult population and its management is based compared with CCB-based treatment in non- a priority in preventing cardiovascular complica- 3 diabetic hypertensive subjects. It thus appears that tions, antihypertensive strategies which also at- treatment with ARBs/ACEIs may prevent new-onset tenuate the trend towards diabetes mellitus might diabetes mellitus better than treatment with CCBs, have considerable clinical significance. Data from which is probably neutral in this aspect. The cohort and randomized trials suggest that the mechanism for the differential effects of the two incidence of type II diabetes mellitus is unchanged different vasodilating agents is, however, unclear, as or increased by thiazides and b-adrenergic blockers, both ARBs and CCBs lower blood pressure by whereas it appears to be unchanged or decreased by reducing peripheral resistance. To our knowledge, no double-blind, randomized study has previously compared the effects of ARB and CCB on insulin Correspondence: Dr TA Aksnes, Department of Cardiology, sensitivity using the hyperinsulinaemic isoglycae- Ullevaal University Hospital, N-0407 Oslo, Norway. mic glucose clamp in patients with essential E-mail: [email protected] Received 20 March 2006; revised 19 June 2006; accepted 19 July hypertension. We hypothesized that ARB therapy 2006; published online 21 September 2006 may have an additive effect and improve insulin Losartan and insulin sensitivity TA Aksnes et al 861 sensitivity more than CCB therapy alone at a At inclusion, blood pressure averaged 16073/ comparable dose with regards to the blood pres- 9672 mm Hg and heart rate 6672 beats/min. Body sure-lowering effect. mass index was 29.271.0 kg/m2 in the whole study group and the waist-to-hip ratio was 0.9270.01 in the women and 1.0570.01 in the men. Four patients Methods (19%) were previously untreated for their hyperten- sion and seven (33%) were previously treated with Study population thiazides, four (19%) with b-blockers and six (29%) Twenty-five patients with mild-to-moderate essen- with a CCB. Five (24%) subjects were smokers. Four tial hypertension (office diastolic blood pressure of the patients did not complete two glucose clamps 95–110 mm Hg and systolic blood pressure owing to technical problems during the clamp o180 mm Hg) were recruited from general practi- procedure. tioners in the city of Oslo. The participants were previously untreated for hypertension or treated with monotherapy, but not with ACEI or ARB. All had impaired glucose tolerance or impaired fasting Study design glucose defined as fasting plasma glucose 6.1– The present double-blind, randomized cross-over 7.0 mmol/l (110–126 mg/dl). The participants also study was designed to compare the metabolic effects had to have either microalbuminuria (urine albumin of 10 mg amlodipine and 100 mg losartan þ 5mg excretion rate X20 mg/min), dyslipidaemia (high- amlodipine (Figure 2). After a 4-week open-label density lipoprotein (HDL)-cholesterol o0.9 mmol/l amlodipine 5 mg run-in period, all hypertensive (35 mg/dl) or triglycerides 41.7 mmol/l (150 mg/ patients were randomized to additional treatment dl)), body mass index 428 kg/m2 or an increased with either amlodipine 5 mg or losartan 100 mg for 8 waist-to-hip ratio (40.9 for men, 40.85 for women). weeks. At the end of this 8-week treatment period, At the first visit a clinical examination and labora- patients underwent blood pressure measurement, tory testing with electrolytes, creatinine and thyroid blood sampling and a hyperinsulinaemic isoglycae- hormones were taken to screen for secondary mic glucose clamp. Following this was a 4-week hypertension. wash-out phase where they continued open-label Owing to side effects of the study medication, 5 mg amlodipine, and then they were crossed-over mainly ankle oedema, but also headaches, flushing to the opposite treatment regimen for another 8 and palpitation, three patients decided to withdraw weeks before the final examination with blood from the study in the run-in period and are not pressure measurement, blood sampling and hyper- included in the final analysis. One of the patients insulinaemic isoglycaemic glucose clamp. who completed the study was excluded from The study was approved by the National Commit- analysis owing to an error at the hospital pharmacy tees for Research Ethics in Norway and the Norwe- (the patient was given amlodipine 10 mg through- gian Medicines Agency, and the patients’ verbal and out). Thus, the final study population consisted of written informed consent to participate was ob- 21 subjects (Figure 1), 11 women and 10 men. tained from each patient before inclusion in the The mean age was 58.6 years (range 46–75 years). study.

Figure 1 Study population.

Journal of Human Hypertension Losartan and insulin sensitivity TA Aksnes et al 862

Figure 2 The double-blind randomized crossover design. All patients used open-label amlodipine 5 mg during the whole trial, and they were randomized double-blindly to additional treatment with either an extra amlodipine 5 mg or losartan 100 mg for the 8-week treatment periods (V1 ¼ visit 1 or at baseline, V2 ¼ visit 2 etc., PE ¼ physical examination, I/E ¼ inclusion/exclusion criteria, BP ¼ blood pressure).

Hyperinsulinaemic isoglycaemic glucose clamp sensitivity has a coefficient of variation of 5% in our technique laboratory, as previously detailed.9,10 The hyperinsulinaemic isoglycaemic glucose clamp was performed after an overnight fast. Antecubital veins on the right and left arm were cannulated Blood pressure measurement and analytical methods with short Teflon catheters (Optiva 2, 18G; Medex Blood pressure was measured with a mercury Medical Ltd., Haslingden, UK). Both catheters were sphygmomanometer with adequate cuff size and kept open with intermittent infusion of isotonic after 5 min rest in sitting position. The pressure was saline, the total amount not exceeding 100 ml. measured at least three times and the values The hyperinsulinaemic isoglycaemic glucose registered were the mean of the two latest measure- clamp was preformed using a modification of the ments. Blood glucose during the hyperinsulinaemic method described by DeFronzo et al.8 The insulin isoglycaemic glucose clamp was measured with an infusion was prepared in a bag with 100 ml of 0.9% Accu-Chek Sensor (Roche Diagnostics GmbH, Man- saline. To prevent insulin from adhering to the nheim, Germany). Serum insulin and C-peptide plastics, 4 ml of saline was exchanged with 4 ml of concentrations were measured using enzyme im- whole blood. To the 100 ml bag, 30 IE of Insulin munoassays (DAKO Insulin and DakoCytomation C- Actrapid were added and the bag was shaken well. peptide. DakoCytomation Ltd, UK). For analysing The mixture was then drawn into a 50 ml syringe glycated haemoglobin (HbA1c) we used Roche and infused at a fixed rate of 0.001 IE/kg body Tinaquant immunoassay. weight/min. The fasting blood glucose level was The homeostasis model assessment for insulin determined as the average of three measurements. resistance (HOMA-IR) was calculated in fasting Glucose and insulin were infused through one conditions as serum glucose (mmol/l) multiplied catheter, whereas the other was used for blood by serum insulin (pmol/l) and divided with 135, as sampling. The insulin infusion was kept unchanged described by Matthews et al.11 during the clamp. Infusion of glucose 200 mg/ml was started after 5 min at a rate of 20 ml/h, and was adjusted every 5 min according to the blood glucose Statistical analysis level. Blood samples were taken every 5 min for the The sample size needed was calculated based on determination of blood glucose concentration, and earlier studies of Moan et al.12 of the effect of at baseline and after 30, 60, 90 and 120 min of losartan on glucose metabolism and insulin sensi- glucose clamping for the determination of serum tivity in hypertensive patients. They had standard insulin. The clamp was performed for 120 min. errors of mean (s.e.m.) ¼ 0.5 for 10 patients, so Insulin sensitivity was expressed as the glucose standard deviation (s.d.) ¼ 1.6. In a 2 Â 2 crossover disposal rate (GDR) (mg/kg/min), calculated from design, if assuming correlation ¼ 0.5, then the the average glucose infusion rate during the within-subject mean square error is 2.5/2 ¼ 1.25. last 20 min. This technique for measuring insulin Assuming alpha ¼ 0.05 and power ¼ 80%, then the

Journal of Human Hypertension Losartan and insulin sensitivity TA Aksnes et al 863 total sample size required is 22 patients (11 per min in the patients given the losartan treatment sequence) if delta ¼ 1. regimen in the second cross-over period. We used SPSS 12.0.1 (SPSS, Chicago, US) soft- ware for data management and statistical analysis. Changes over time were analysed using paired- Other assessments of the glucose homeostasis samples t test. Variables with a skewed distribution There was no significant difference in the calculated were analysed after logarithmical transformation, HOMA-IR between the treatment regimens. How- and were back-transformed to natural units for ever, HOMA-IR was significantly lower during the presentation in text and tables. Non-parametric losartan treatment period and nonsignificantly low- analysis with Wilcoxon-matched pairs signed rank er during the amlodipine treatment period, com- sum test were used for non-normally distributed pared to the first visit (Table 1). There was no data. A two-tailed P-valueo0.05 was considered the significant difference between treatment with amlo- limit of statistical significance. All values are dipine 10 mg and losartan 100 mg þ amlodipine presented as mean7s.e.m. unless stated otherwise. 5 mg, with regards to fasting serum insulin as shown Carry-over effects may appear with the crossover in Table 1. However, fasting serum insulin was design and we therefore used a wash-out period of significantly lower after treatment with losartan 4 weeks between the 8 weeks treatment periods in 100 mg þ amlodipine 5 mg compared to the first order to minimize carry-over effects and a possible visit, whereas there was a nonsignificant reduction carry-over effect is considered in the results. of serum insulin after treatment with amlodipine 10 mg. Fasting C-peptide was significantly reduced

Results Insulin sensitivity The GDR was significantly higher during treat- ment with losartan 100 mg þ amlodipine 5 mg compared to amlodipine 10 mg (4.970.4 vs 4.270.5 mg/kg/min, P ¼ 0.039) (Figure 3). Nine of the 17 patients who successfully completed two glucose clamp examinations were treated with amlodipine in their first cross-over period. GDR on amlodipine 10 mg treatment was the same for the patients randomized to this treatment in their first cross-over period (4.270.8 mg/kg/min, n ¼ 9) and those randomized this in the last cross-over period (4.270.6 mg/kg/min, n ¼ 8). The GDR on losartan 100 mg þ amlodipine 5 mg was 4.570.4 mg/kg/min Figure 3 Insulin sensitivity assessed by the hyperinsulinaemic in the patients given the losartan treatment regimen isoglycaemic glucose clamp in 17 hypertensive patients treated in the first cross-over period and 5.270.6 mg/kg/ with amlodipine 10 mg or losartan 100 mg þ amlodipine 5 mg.

Table 1 Metabolic data at inclusion (visit 1) and after 8 weeks treatment of the two different regimens (n ¼ 21)

Visit 1 Amlodipine 10 mg Losartan 100 mg+Amlodipine 5 mg

P* P* Pw

HOMA-IR 4.470.8 3.170.6 NS 2.870.5 0.007 NS Insulin (pmol/l) 94.4716.1 67.5713.3 NS 59.878.1 0.009 NS C-peptide (pmol/l) 1243.87150.2 934.6792.7 0.032 944.8786.2 0.023 NS Glucose (mmol/l) 6.170.3 6.070.3 NS 5.970.3 NS NS HbA1c (%) 5.770.1 5.670.1 NS 5.570.1 NS NS Total cholesterol (mmol/l) 6.070.3 5.670.2 0.041 5.470.2 0.002 NS HDL-cholesterol (mmol/l) 1.570.1 1.570.1 NS 1.470.1 0.036 NS LDL-cholesterol (mmol/l) 3.870.3 3.670.2 NS 3.470.2 0.002 NS Triglycerides (mmol/l) 1.5970.14 1.3070.16 0.036 1.5970.31 NS NS Uric acid (mmol/l) 364720 315715 0.001 306720 0.002 NS Urine albumin: creatinine ratio (mg/mmol) 1.1470.55 1.2670.66 NS 0.8270.30 NS NS BMI (kg/m2) 29.271.0 29.271.0 NS 29.071.0 NS NS

Abbreviations: BMI, body mass index; GDR, glucose disposal rate; HbA1c, glycated haemoglobin; HDL, high-density lipoprotein; HOMA-IR, Homeostasis model assessment for insulin resistance; I, insulin; LDL, low-density lipoprotein. P*, P-value for differences between visit 1 and study-treatment. Pw, P-value for differences between treatment with amlodipine 10 mg and losartan 100 mg+amlodipine 5 mg.

Journal of Human Hypertension Losartan and insulin sensitivity TA Aksnes et al 864 during both treatment periods compared inclusion considered to be the ‘gold standard’ in assessing into the study, but there was no significant differ- insulin sensitivity.8,14,15 In this method, a high ence between the two treatment regimens. There steady circulating insulin level is maintained by were no significant differences in fasting glucose constant insulin infusion and the blood glucose and HbA1c between treatment with amlodipine concentration is frequently measured and main- 10 mg and losartan 100 mg þ amlodipine 5 mg tained at the fasting level (isoglycaemic), or at a (Table 1). predetermined (euglycaemic) level, by infusion of glucose at a variable rate. The amount of glucose needed to maintain isoglycaemia per unit of time is Blood pressure and heart rate an index of sensitivity to the administered insulin. There were no significant differences in blood Insulin-mediated glucose uptake during the hy- pressure between treatment with amlodipine perinsulinaemic isoglycaemic glucose clamp occurs 10 mg (14172/8871 mm Hg) and losartan 100 mg þ mainly in skeletal muscle,8 and is in part dependent amlodipine 5 mg (14373/8871 mm Hg). But highly on muscular blood flow. Thus, an increase in blood significant reductions in systolic and diastolic blood flow induced by vasodilating drugs would be pressure were observed in both treatment regimens expected to increase glucose uptake. The observed from inclusion in the study (16073/9672 mm Hg, effect in the present study was beyond the vascular Po0.001). There were no significant differences in effects and blood pressure reduction achieved by resting heart rate during the visits. The heart rate maximal calcium channel blockade with amlodi- was 6672, 6872 and 6972 beats/min at visit 1 and pine, indicating a non-haemodynamic effect of when treated with amlodipine 10 mg and losartan angiotensin II-receptor blocking with losartan on 100 mg þ amlodipine 5 mg, respectively. insulin sensitivity. We chose amlodipine as the comparator for losartan, as it is considered to have a neutral effect Serum lipids on insulin sensitivity,4 though studies have shown There were no significant changes in total serum inconsistent results. In fact in earlier clamp stu- cholesterol, HDL-cholesterol, low-density lipopro- dies16 comparing amlodipine with other antihyper- tein (LDL)-cholesterol and triglycerides between the tensive drugs in parallel group study designs, amlodipine and losartan treatment periods (Table 1). insulin sensitivity was significantly improved from However, total serum cholesterol was significantly baseline after treatment with amlodipine. In our reduced from the time of inclusion into the study to study the patients were hypertensive and placebo treatment with both amlodipine 10 mg and losartan was not an option. By using another vasodilating 100 mg þ amlodipine 5 mg (Table 1). There was a agent as a comparator, we were able to study the significant reduction of LDL-cholesterol from inclu- metabolic effect of the ARB, beyond the vasodilating sion to treatment with losartan 100 mg þ amlodipine effect of a CCB. We chose 5 mg amlodipine as open- 5 mg, but not from inclusion to treatment with label throughout the study, and added amlodipine amlodipine 10 mg. Conversely, there was a signifi- 5 mg or losartan 100 mg (blinded) in a randomized cant reduction of triglycerides from inclusion to cross-over design as shown in Figure 2. The dosage treatment with amlodipine 10 mg, but not to the of 100 mg losartan was used in order to achieve an losartan regimen. optimal angiotensin II-receptor blocking effect. The additional 5 mg of amlodipine in the other crossover arm compared to losartan 100 mg was given in order Uric acid to avoid a difference in blood pressure between the There were no significant changes in serum uric regimens. acid between the amlodipine and losartan treatment As our aim was to do a direct comparison of the groups. However, serum uric acid was significantly two different vasodilating principles, and in order to reduced from baseline to treatment with both the minimize the strain on the participants, we chose amlodipine (D 49713 mmol/l) and treatment regi- not to conduct the glucose clamp at baseline. The men losartan (D 58716 mmol/l) (Table 1). crossover design has been widely used in similar contexts. One of its advantages is the increased Discussion statistical power obtained by within-subject com- parison rather than group comparison. A disadvan- Diabetes mellitus, and in particular type II diabetes, tage of the design is that every patient has to has emerged as a major health problem and tends to complete both treatment periods and all examina- cluster with hypertension in individuals at high risk tions, and unfortunately we lost four patients owing of cardiovascular disease.13 In this study we found to technical problems during one of the two clamp that in hypertensive patients with a high risk of procedures. The two treatment periods were sepa- developing diabetes mellitus, treatment with the rated by a 4-week wash-out period intended to ARB losartan significantly improved insulin sensi- minimize carry-over effects. The order in which the tivity in skeletal muscle as assessed by the glucose drugs were given apparently had no effect on GDR clamp technique. The glucose clamp technique is during treatment with amlodipine 10 mg. However,

Journal of Human Hypertension Losartan and insulin sensitivity TA Aksnes et al 865 GDR on losartan 100 mg þ amlodipine 5 mg was hospital on two separate days for each examination higher in the patients who were given losartan in and we therefore chose to focus on the ‘gold the last crossover period. The number of patients is standard’, the glucose clamp, for examination of too small to prove statistical significance (eight insulin sensitivity. patients got losartan in the first cross-over period, The present study confirms the findings and and nine in the last period), but regardless the hypothesis in our early studies, which suggested results do not suggest any carry-over effects. that losartan improves insulin sensitivity,12,24 parti- CCBs are considered to be neutral in their effects cularly in patients with severe hypertension24 or on glucose homeostasis. A recent meta-analysis17 insulin resistance.12 In the Insulin Carotids US even suggests that in hypertension, treatment with Scandinavia (ICARUS)-study,25 a Losartan Interven- CCB is associated with lower rates of new-onset tion For Endpoint-Reduction in Hypertension (LIFE) diabetes mellitus in comparison to diuretics and b- substudy, long-term treatment with losartan for 3 adrenergic blockers. Valsartan, another ARB, has years maintained insulin sensitivity in hypertensive been shown to be associated with lower rates patients with electrocardiographic left ventricular of new-onset diabetes mellitus compared to hypertrophy, whereas on treatment with atenolol amlodipine in the VALUE trial,7 suggesting that insulin sensitivity decreased. Atenolol and other b- blockade of the renin–angiotensin system affects blockers are known to increase the risk of diabetes glucose metabolism separately from the blood mellitus.5 However, the 25% relative risk reduction pressure lowering effect. Angiotensin II in excess of new-onset diabetes mellitus in the losartan-based may impair endothelial function and promote regimen in the LIFE study26 may also be explained vascular disease. Conversely, angiotensin II-receptor by preserved insulin sensitivity by losartan. blockade may improve endothelial function and In the present study, treatment with amlodipine structural abnormalities in hypertensive patients.18 plus losartan resulted in an identical blood pressure Thus, a reasonable explanation for the observed reduction, but improved insulin sensitivity, com- prevention of new-onset diabetes mellitus may lie in pared to a maximal dose of amlodipine. Thus our the improvement of microcirculatory flow and a data suggest that AT-1 receptor blockade with better delivery of glucose and insulin to skeletal losartan affects glucose metabolism beneficially muscle.19 through mechanisms at the cellular level, beyond An alternative, and possible additional, explana- what can be expected by the vascular vasodilating tion is an improvement of glucose homeostasis at effects alone.19 the cellular level through agonistic interaction with peroxisome proliferator-activated receptor-gam- ma.20,21 In an experimental model, saralasin, a non- Acknowledgements selective angiotensin II-antagonist, has been shown to affect pancreatic b-cells through increased pan- We thank biochemist Roseli Andreassen for techni- creatic islet blood flow.22 It has also been proposed cal assistance and the Department of Clinical that blockade of the renin–angiotensin system may Chemistry at Ullevaal University Hospital and Dr promote the recruitment and differentiation of Knut Lande for analyzing glucose, HbA1c, lipids adipocytes. This would counteract the ectopic and uric acid. We also thank Merck & Co., USA for deposition of lipids in other tissues like liver, school grant support. We are indebted to physicians muscle and pancreas, and thereby improve insulin and staff at Bentsebro legesenter, Collosseumklinik- sensitivity and prevent type II diabetes mellitus.23 ken, Ekeberg legesenter, L11 Familiehelsesenter, However, assessment of a potential effect on insulin Manglerud legekontor, Nordseter legekontor, secretion was beyond the scope of the present Nordstrand legekontor and Trosterud legekontor in study. Oslo for their kind help with recruiting patients. Insulin sensitivity assessed by the hyperinsuli- naemic isoglyceamic glucose clamp was the primary end point of our study, and we did not observe any significant improvement of glycaemic control, as What is known about topic K Different antihypertensive treatment regimens have different assessed from the fasting glucose and HbA1c effect on glucose homeostasis and development of new-onset concentrations. A modest improvement of insulin diabetes mellitus. sensitivity over a 2-month period may not be K Blockade of the renin–angiotensin system may improve reflected by improved fasting glucose levels. More- insulin sensitivity, but the mechanism is not clear. over, HbA1c is an integrated measure of glycaemic What this study adds control over the last 6–8 weeks before measurement, K There is additive beneficial effects of angiotensin II-receptor and may not be sensitive enough to detect a recent blockade with losartan on insulin sensitivity compared with and gradual change in insulin sensitivity. Oral amlodipine alone, despite similar blood pressure reduction. was not included in our study K AT-1 receptor blockade with losartan must have other beneficial effects on the glucose metabolism at the cellular in order to minimize the strain on the recruited non- level, beyond what can be expected by the vasodilatation paid volunteers. If we had included an oral glucose alone. tolerance test, the patients had to meet at the

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