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 insulin 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; diabetes mellitus; hypertension; insulin resistance 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.