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Journal of Human (2003) 17, 433–435 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh RESEARCH LETTER and comparative efficacy and safety in type II diabetic hypertensive patients

Journal of Human Hypertension (2003) 17, 433–435. hypoglycaemic agents (second-generation sulphanil- doi:10.1038/sj.jhh.1001572 ), were not taking antihypocholesterolaemic drugs, and did not have evidence of macroangio- Dear Sir, pathy (by electrocardiogram and Doppler examina- tion), or nephropathy (by microalbuminuria, Cardiovascular and risks are defined as AER o30 mg/24 h), or neuropathy (by almost doubled when the hypertensive patient is vibration perception threshold).5 also affected by diabetes mellitus. Lowering of blood The study had a randomized, double-blind design pressure markedly decreases the rate of cardiovas- for parallel groups: after an initial 4-week wash-out cular events and renal deterioration in these placebo period, patients were randomly given patients.1 Recent comparative studies in diabetes perindopril, 4 mg once daily, or candesartan, 16 mg suggest that, for the prevention of cardiovascular once daily for 12 months. events, converting (ACE) inhibitors may At the end of the placebo and active treatment be superior to alternative antihypertensive agents, periods, body mass index (BMI), fasting plasma 2 independently of their antihypertensive effect. glucose (FPG), HbA1c, fasting plasma insulin (FPI), Compared to ACE inhibitors, angiotensin receptor homeostasis model assessment (HOMA index), SBP, blockers (ARBs) offer more complete and pharma- DBP, lipid profile with lipoprotein (Lp(a)), plasma cologically desirable blockade of the –angio- plasminogen activator inhibitor 1 (PAI-1), Hct levels, tensin system, and they are free from the adverse and AER were evaluated. All variables (except for effect of cough observed with the administration of HbA1c at 1 month) were evaluated at the end of the ACE inhibitors.3 Metabolic abnormalities as insulin placebo period (baseline), and 1, 6, and 12 months resistance, impairment lipid profile, and decreased later, and after a wash-out period of 1 month. fibrinolytic activity can be improved by ACE Blood pressure was monitored at each clinical inhibitors.2 ARBs have been shown to retard the visit (every month) in the seated position (right progression of albuminuria and the development arm), by using a standard mercury sphygmoman- and progression of nephropathy,4 but there are few ometer with a cuff of appropriate size. Measure- data of the ARBs action on metabolic parameters, ments were always taken by the same investigator in especially in comparison with ACE inhibitors, in the morning before daily drug intake (ie B24 h after diabetic subjects. dosing) and after the subject had rested 10 min in a The aim of our study was to compare glucose quiet room. Three successive blood pressure read- homeostasis, serum lipid profile, fibrinolytic activ- ings were obtained at 1 min intervals and averaged. ity, albumin rate (AER), and homocysteine All plasma parameters were determined after a (Hct) in patients with mild hypertension and type II 12-h overnight fast with the standardized method as diabetes, during therapy with perindopril (a long- described in Fogari et al.6 The estimate of insulin acting ACE inhibitor) and candesartan (a long-acting resistance was calculated by HOMA index with the ARB). formula: FPI (mU/ml) Â FPG (mmol/l)/22.5. HOMA A total of 96 patients (M : F ¼ 47 : 49) with type II index is an inexpensive alternative to more sophis- diabetes according to the American Diabetes Asso- ticated techniques and has a good correlation with ciation criteria,5 who had been diagnosed within the glucose-clamp technique, the gold standard in the last 6 months and with mild essential hypertension assessment of insulin sensitivity.7 according to the World Health Organization criteria One-way analysis of variance (ANOVA) followed (DBP490 and o105 mmHg) on repeated measure- by t-test was carried out to assess eventual differ- ments in the absence of any antihypertensive ence from baseline values and between the two treatment, were recruited for the study. They were treatment groups. A value of Po0.05 has been all in adequate glycaemic control (glycosylated considered as significant for each test. haemoglobin (HbA1c) o7.5%) with diet or oral After 4 weeks of placebo treatment, patients were entered into treatment period and randomly allo- Received 17 September 2002; revised 14 December 2002; accepted 4 February 2003 cated to take either perindopril (N ¼ 49; mean Research Letter

434 age ¼ 53 7 10 years) or candesartan (N ¼ 47; mean age ¼ 55 7 9 years). There was no significant differ- ence between clinical characteristics (age, sex dis- 0.05 2.0***** 0.28 0.03 0.003 1.1 0.6 0.5***** 0.69 0.04 0.002 2.4 0.0001 7 7 7 7 7 7 7 7 7 7 7 7 tribution, BMI), haemodynamic parameters (BP, 7 0.01 compared heart rate) and laboratory data before perindopril 5 À o 0.1 7.0 2.0 1.1 3.0 0.56 0.05 0.04 2.08 0.15 P À À À À and candesartan administration. À À À À À À No subject experienced adverse effects serious enough to warrant discontinuing either drug, but ***** , ***** some side effects were manifested: dry cough, , abnormal taste, or epigastric discomfort in five 0.05 1.5***** 0.17 3.47* 0.02***** 0.002***** 0.7***** 0.1 1.0***** 0.1* 0.002 0.03 2.6 0.023 0.01 7 7 7 7 7 7 7 7 7 7 7 7 patients of the perindopril group and headache, 7 6

dizziness, or nausea in three patients of the À 0.1 5.0 1.0 0.9 4.0 0.39 7.64 0.03 0.04 0.51 0.03 0.06 À À À À À À À À À À À candesartan group. values were not À altered and remained within the normal range during all phases of the trial. Our main results have been summarized in Table 1 0.1 0.11 2.78 0.05 0.02 0.9 0.1 4.1****** 4.1**** 2.9**** 0.08 0.01 (expressed as means 7 s.d.). Both tested drugs 0.009 7 7 7 7 7 7 7 7 7 7 7 7 7

significantly reduced BP and this reduction was 8 À 0.2 3.0 0.9 8.0 12.0 0.44 4.86 0.10 0.25 À À À already visible at first month. À À À À À We previously observed that FPG and HbA À 1c month 1 month wash-out 0.02 compared to values before treatments; **** *

values did not differ after treatment between *** *** *** *** 0.07 , , , , o **** ***

6 , , perindopril and . Although our patients P 0.1 3.6* 2.4****** 0.02 3.6****** 0.22* 4.5**** 0.2* 6.25* 0.01 0.05 0.19* 0.13 0.02 were in good glucose control with diet and oral 0.07* 7 7 7 7 7 7 7 7 7 7 7 7 hypoglycaemic agents, we obtained a further reduc- 7 8 À 0.2 5.0 0.3 tion of FPG with perindopril at 12th month 0.8 11.0 0.83 13.0 9.72 0.05 0.36 0.25 0.18 À À À À À À À À À À À compared to candesartan (À9.7 and À5.0%, respec- À tively). As expected, candesartan therapy did not 8 0.06 1.7*** 0.8 0.2 3.8 0.17 0.05 3.9*** 0.35 0.02 0.03 0.02 modify glycaemic profile during the study. 0.03 7 7 7 7 7 7 7 7 7 7 7 7 Several studies comparing the effects of ACE 7 Changes 10 2.0 7.2 inhibitors and ARBs have been undertaken to 5.0 À 0.12 0.05 0.33 0.13 2.78 0.03 0.07 À À À À À À À À À elucidate the mechanism of the beneficial effect of À

ACE inhibitors on insulin sensitivity. In our study, month 12 * perindopril improved HOMA index compared to 0.05 compared to values before treatments. o 0.05 2.20*** 1.9 0.01 2.6 4.1*** 0.22 0.1 0.69 0.01 0.08 0.13 0.05 0.04 0.04 candesartan (À20.7 vs À6.2%), while Higashiura P 7 7 7 7 7 7 7 7 7 7 7 7 et al9 found that candesartan significantly improves 7 0.1 6.0 4.0 0.2 6.8 0.5 11.0 0.44 6.25 0.04 0.16 0.18 insulin resistance with glucose-clamp technique in 0.11 À À À À À À 0.05 compared to values before treatments; *** À À À À À À À

patients with essential hypertension, through ACE o inhibition. Moreover, after 12 months of perindopril P 0.7 0.1 2.1 3.6** 0.8** 0.11 0.01 0.07 0.003 0.02 0.05 therapy, we noted a statistically significant improve- 0.01 7 7 7 7 7 7 7 7 7 7 7 ment of plasma LDL-C (À11.7%) and Lp(a) (À17.2%) 7 1.6 0.3 5.1 8.0 3.0 0.22 0.08 1.39 0.05 À À À compared to candesartan (À3.2 and +6.7%, respec- À À À À À tively), but ACE inhibitors are already known to À 10 month 6

improve plasma LDL-C and Lp(a) levels. * 0.06 1.2 0.01 1.9 3.5** 1.8** 0.09 0.49 0.01 0.02 0.04 0.09 0.08 0.01 0.02 7 7 7 7 7 7 7 7 7 7 7 With regard to plasma fibrinolytic parameters, in 7 our study, we observed a reduction of PAI-1 at 12th FF 2.0 0.1 4.5 8.0 5.0 0.3 0.28 3.47 0.03 0.08 0.11 0.04 À À À À À month with perindopril (À13.2%) compared to an À À À À À À À increase at the same month with candesartan 1.10 0.72 42.36 0.13 13 6 11 6 5 2.5 0.39 0.11 (7.7%). It confirms our previous report where we 0.36 7 7 7 7 7 7 7 7 7 7 7 7 7 demonstrated that perindopril decreased PAI-1 0.05 compared to values at 12th month; ****** o

compared to losartan, in hypertensive, type II P 6 candesartan 16 mg (C): blood pressure and metabolic parameters before, after the treatments, and during the wash-out period

diabetic patients. vs Finally, as expected,4,6 AER was decreased at the 0.05 compared to values between treatments; ** Baseline 1 0.90 6.50 0.83 8.88 40.2873.62 0.10 1.04 11510 39 10.9 18 6493 148 2.2 3.99 0.47 3.24 0.20 1.68 0.43 1.07

end of the study in both groups (À47.1 and À44.5%, o PCP C P C P C P C P 7 7 7 7 7 7 7 7 7 7 7 7 respectively). Our patients started as normoalbumi- 7 nuric and remained normoalbuminuric for all the s.d.; *

phases of the study, probably because the glycaemic 7 control was good and the antihypertensive therapy

stopped the possible progression to microalbumi- Perindropil 4 mg (P) mol/l) 1.04 (%) 6.40 m nuria. mol l) 11.5 m In conclusion, to the best of our knowledge, this is 1c to values before treatments; ***** Table 1 Data are means FPG (mmol/l) 8.60 FPI (pmol/l) 70.84 HDL-C (mmol/l) 1.11 PAI-1 (ng/ml)Hct ( AER (mg/24 h) 38 17 SBP (mmHg)DBP (mmHg) 147 94 HbA HOMA index 3.86 LDL-C (mmol/l) 3.11 Tg (mmol/l) 1.81 a first study comparing perindopril and candesartan Lp(a) (

Journal of Human Hypertension Research Letter

435 on hypertensive, type II diabetic patients. These sive type 2 diabetic patients. Am J Hypertens 2002; 15: data suggest that potentiation of the kinin system by 316–320. 7 Bonora E et al. Homeostasis model assessment closely mirrors ACE inhibition may play an important role in the the glucose clamp technique in the assessment of insulin positive effects of ACE inhibitors on insulin sensi- sensitivity. 2000; 23: 57–63. tivity, fibrinolytic balance, improvement of lipid 8 Trenkwalder P, Lehtovirta M, Dahl K. Long-term treatment profile, and on Lp(a) reduction, beyond blood with candesartan cilexetil does not affect glucose homeostasis pressure control. However, we do not exclude a or serum lipid profile in mild hypertensives with type II diabetes. J Hum Hypertens 1997; 11 (Suppl. 2): S81–S83. contribution of angiotensin II or involvement of 9 Higashiura K, Ura N, Miyazaki Y, Shimamoto K. Effect of an other angiotensin receptor subtypes in these effects. angiotensin II receptor antagonist, candesartan, on insulin Further studies are needed to verify these points. resistance and pressor mechanisms in essential hypertension. J Hum Hypertens 1999; 13 (Suppl. 1): S71–S74. 10 Derosa G et al. Effects of on blood pressure, lipid profile, and lipoprotein (a) levels in normotensive patients References with type 2 diabetes and microalbuminuria: an open-label, 1 Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of uncontrolled study. Curr Ther Res Clin Exp 2002; 63: 216–226. hypertension in adult patients with diabetes. Diabetes Care 2002; 25: 134–147. G Derosa, AFG Cicero, A Mugellini, L Ciccarelli and 2 Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive R Fogari patients with diabetes. Lancet 1998; 351: 689–690. 3 Pylypchuk GB. ACE inhibitorFversus angiotensin II block- Department of Internal Medicine and Therapeutics erFinduced cough and angioedema. Ann Pharmacother 1998; University of Pavia, Pavia, Italy 32: 1060–1066. Department of Clinical Medicine and Applied 4 Gradman AH. AT(1)-receptor blockers: differences that matter. J Hum Hypertens 2002; 16 (Suppl. 3): S9–S16. Biotechnolgy ‘D Campanacci’, University of 5 The Expert Committeee on the diagnosis and classification of Bologna, Bologna Italy diabetes mellitus. Report of the Expert Committeee on the Correspondence: G Derosa Dr G Derosa diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (Suppl. 1): 5–20. Department of Internal Medicine and Therapeutics 6 Fogari R et al. Losartan and perindopril effects on plasma University of Pavia, P le C Golgi, 2, 27100 Pavia Italy plasminogen activator inhibitor-1 and fibrinogen in hyperten- E-mail: [email protected]

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