Perindopril and candesartan comparative efficacy and safety in type II diabetic hypertensive patients

Journal of Human Hypertension (2003) 17, 433–435 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh

RESEARCH LETTER

Perindopril and candesartan comparative efficacy and safety in type II diabetic hypertensive patients Journal of Human Hypertension (2003) 17, 433–435. doi:10.1038/sj.jhh.1001572 Dear Sir, Cardiovascular and cerebrovascular disease risks are almost doubled when the hypertensive patient is also affected by diabetes mellitus. Lowering of blood pressure markedly decreases the rate of cardiovascular events and renal deterioration in these patients.1 Recent comparative studies in diabetes suggest that, for the prevention of cardiovascular events, angiotensin converting (ACE) inhibitors may be superior to alternative antihypertensive agents, independently of their antihypertensive effect.2 Compared to ACE inhibitors, angiotensin receptor blockers (ARBs) offer more complete and pharmacologically desirable blockade of the renin–angiotensin system, and they are free from the adverse effect of cough observed with the administration of ACE inhibitors.3 Metabolic abnormalities as insulin resistance, impairment lipid profile, and decreased fibrinolytic activity can be improved by ACE inhibitors.2 ARBs have been shown to retard the progression of albuminuria and the development and progression of nephropathy,4 but there are few data of the ARBs action on metabolic parameters, especially in comparison with ACE inhibitors, in diabetic subjects. The aim of our study was to compare glucose homeostasis, serum lipid profile, fibrinolytic activity, albumin excretion rate (AER), and homocysteine (Hct) in patients with mild hypertension and type II diabetes, during therapy with perindopril (a longacting ACE inhibitor) and candesartan (a long-acting ARB). A total of 96 patients (M : F ¼ 47 : 49) with type II diabetes according to the American Diabetes Association criteria,5 who had been diagnosed within the last 6 months and with mild essential hypertension according to the World Health Organization criteria (DBP490 and o105 mmHg) on repeated measurements in the absence of any antihypertensive treatment, were recruited for the study. They were all in adequate glycaemic control (glycosylated haemoglobin (HbA1c) o7.5%) with diet or oral Received 17 September 2002; revised 14 December 2002; accepted 4 February 2003

hypoglycaemic agents (second-generation sulphanilureas), were not taking antihypocholesterolaemic drugs, and did not have evidence of macroangiopathy (by electrocardiogram and Doppler examination), or nephropathy (by microalbuminuria, defined as AER o30 mg/24 h), or neuropathy (by vibration perception threshold).5 The study had a randomized, double-blind design for parallel groups: after an initial 4-week wash-out placebo period, patients were randomly given perindopril, 4 mg once daily, or candesartan, 16 mg once daily for 12 months. At the end of the placebo and active treatment periods, body mass index (BMI), fasting plasma glucose (FPG), HbA1c, fasting plasma insulin (FPI), homeostasis model assessment (HOMA index), SBP, DBP, lipid profile with lipoprotein (Lp(a)), plasma plasminogen activator inhibitor 1 (PAI-1), Hct levels, and AER were evaluated. All variables (except for HbA1c at 1 month) were evaluated at the end of the placebo period (baseline), and 1, 6, and 12 months later, and after a wash-out period of 1 month. Blood pressure was monitored at each clinical visit (every month) in the seated position (right arm), by using a standard mercury sphygmomanometer with a cuff of appropriate size. Measurements were always taken by the same investigator in the morning before daily drug intake (ie B24 h after dosing) and after the subject had rested 10 min in a quiet room. Three successive blood pressure readings were obtained at 1 min intervals and averaged. All plasma parameters were determined after a 12-h overnight fast with the standardized method as described in Fogari et al.6 The estimate of insulin resistance was calculated by HOMA index with the formula: FPI (mU/ml)  FPG (mmol/l)/22.5. HOMA index is an inexpensive alternative to more sophisticated techniques and has a good correlation with glucose-clamp technique, the gold standard in the assessment of insulin sensitivity.7 One-way analysis of variance (ANOVA) followed by t-test was carried out to assess eventual difference from baseline values and between the two treatment groups. A value of Po0.05 has been considered as significant for each test. After 4 weeks of placebo treatment, patients were entered into treatment period and randomly allocated to take either perindopril (N ¼ 49; mean

Journal of Human Hypertension

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Data are means 7 s.d.; *Po0.05 compared to values between treatments; **Po0.05 compared to values before treatments; ***Po0.02 compared to values before treatments; ****Po0.01 compared to values before treatments; *****Po0.05 compared to values at 12th month; ******Po0.05 compared to values before treatments.

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P

6* month 1* month Baseline

SBP (mmHg) 147 7 6 148 7 6 8.0 7 3.5** 8.0 7 3.6**11.0 7 4.1*** 10 7 3.9***13.0 7 4.5**** 12.0 7 4.1**** 5.0 7 1.5***** 7.0 7 2.0***** 4.0 7 1.0***** 3.0 7 0.5***** DBP (mmHg) 94 7 4 93 7 5 5.0 7 1.8** 3.0 7 0.8** 6.0 7 2.20*** 5.0 7 1.7***11.0 7 3.6*,**** 8.0 7 2.9**** 6.40 7 0.90 6.50 7 1.10 F F 0.1 7 0.05 0.12 7 0.06 0.2 7 0.1 0.2 7 0.1 0.1 7 0.05 0.1 7 0.05 HbA1c (%) 0.39 7 0.17 0.56 7 0.28 FPG (mmol/l) 8.60 7 0.83 8.88 7 0.72 0.28 7 0.06 0.22 7 0.11 0.44 7 0.22 0.33 7 0.17 0.83 7 0.22*,*** 0.44 7 0.11 , , 7.64 7 3.47* *****2.08 7 0.69 FPI (pmol/l) 70.84 7 40.2873.62 7 42.363.47 7 0.49 1.39 7 0.07 6.25 7 0.69 2.78 7 0.35 9.72 7 6.25* *** 4.86 7 2.78 0.51 7 0.1*,***** 0.15 7 0.04 HOMA index 3.86 7 2.2 3.99 7 2.5 0.3 7 0.09 0.08 7 0.01 0.5 7 0.1 0.13 7 0.05 0.8 7 0.2*,*** 0.25 7 0.08 0.03 7 0.02***** 0.05 7 0.03 LDL-C (mmol/l) 3.11 7 0.47 3.24 7 0.39 0.08 7 0.04 0.05 7 0.02 0.16 7 0.08 0.07 7 0.03 0.36 7 0.19*,*** 0.10 7 0.05 HDL-C (mmol/l) 1.11 7 0.10 1.04 7 0.13 0.03 7 0.01 0.02 7 0.0030.04 7 0.01 0.03 7 0.02 0.05 7 0.01 0.05 7 0.01 0.03 7 0.002 0.03 7 0.002 Tg (mmol/l) 1.81 7 0.20 1.68 7 0.11 0.11 7 0.09 0.08 7 0.05 0.18 7 0.13 0.05 7 0.02 0.25 7 0.13 0.02 7 0.009 0.06 7 0.023 0.01 7 0.0001 0.04 7 0.002***** 0.04 7 0.003 Lp(a) (mmol/l) 1.04 7 0.43 1.07 7 0.36 0.04 7 0.01 0.02 7 0.01 0.11 7 0.04 0.04 7 0.03 0.18 7 0.07*,*** 0.07 7 0.02 PAI-1 (ng/ml) 38 7 11 39 7 13 2.0 7 1.2 1.6 7 0.7 4.0 7 1.9 2.0 7 0.8 5.0 7 2.4****** 3.0 7 0.9 1.0 7 0.7***** 2.0 7 1.1 Hct (mmol l) 11.5 7 5 10.9 7 6 0.1 7 0.01 0.3 7 0.1 0.2 7 0.01 0.05 7 0.2 0.3 7 0.02 0.9 7 0.1 0.9 7 0.1 1.1 7 0.6 AER (mg/24 h) 17 7 10 18 7 11 4.5 7 1.9 5.1 7 2.1 6.8 7 2.6 7.2 7 3.8 8 7 3.6****** 8 7 4.1****** 6 7 2.6 5 7 2.4

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1 month wash-out 12* month Changes

age ¼ 53 7 10 years) or candesartan (N ¼ 47; mean age ¼ 55 7 9 years). There was no significant difference between clinical characteristics (age, sex distribution, BMI), haemodynamic parameters (BP, heart rate) and laboratory data before perindopril and candesartan administration. 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 patients of the perindopril group and headache, dizziness, or nausea in three patients of the candesartan group. Creatinine values were not altered and remained within the normal range during all phases of the trial. Our main results have been summarized in Table 1 (expressed as means 7 s.d.). Both tested drugs significantly reduced BP and this reduction was already visible at first month. We previously observed that FPG and HbA1c values did not differ after treatment between perindopril and losartan.6 Although our patients were in good glucose control with diet and oral hypoglycaemic agents, we obtained a further reduction of FPG with perindopril at 12th month compared to candesartan (9.7 and 5.0%, respectively). As expected, candesartan therapy did not modify glycaemic profile during the study.8 Several studies comparing the effects of ACE inhibitors and ARBs have been undertaken to elucidate the mechanism of the beneficial effect of ACE inhibitors on insulin sensitivity. In our study, perindopril improved HOMA index compared to candesartan (20.7 vs 6.2%), while Higashiura et al9 found that candesartan significantly improves insulin resistance with glucose-clamp technique in patients with essential hypertension, through ACE inhibition. Moreover, after 12 months of perindopril therapy, we noted a statistically significant improvement of plasma LDL-C (11.7%) and Lp(a) (17.2%) compared to candesartan (3.2 and +6.7%, respectively), but ACE inhibitors are already known to improve plasma LDL-C and Lp(a) levels.10 With regard to plasma fibrinolytic parameters, in our study, we observed a reduction of PAI-1 at 12th month with perindopril (13.2%) compared to an increase at the same month with candesartan (7.7%). It confirms our previous report where we demonstrated that perindopril decreased PAI-1 compared to losartan, in hypertensive, type II diabetic patients.6 Finally, as expected,4,6 AER was decreased at the end of the study in both groups (47.1 and 44.5%, respectively). Our patients started as normoalbuminuric and remained normoalbuminuric for all the phases of the study, probably because the glycaemic control was good and the antihypertensive therapy stopped the possible progression to microalbuminuria. In conclusion, to the best of our knowledge, this is a first study comparing perindopril and candesartan

Table 1 Perindropil 4 mg (P) vs candesartan 16 mg (C): blood pressure and metabolic parameters before, after the treatments, and during the wash-out period

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Research Letter

Research Letter

on hypertensive, type II diabetic patients. These data suggest that potentiation of the kinin system by ACE inhibition may play an important role in the positive effects of ACE inhibitors on insulin sensitivity, fibrinolytic balance, improvement of lipid profile, and on Lp(a) reduction, beyond blood pressure control. However, we do not exclude a contribution of angiotensin II or involvement of other angiotensin receptor subtypes in these effects. Further studies are needed to verify these points.

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References 1 Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of hypertension in adult patients with diabetes. Diabetes Care 2002; 25: 134–147. 2 Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive patients with diabetes. Lancet 1998; 351: 689–690. 3 Pylypchuk GB. ACE inhibitorFversus angiotensin II blockerFinduced cough and angioedema. Ann Pharmacother 1998; 32: 1060–1066. 4 Gradman AH. AT(1)-receptor blockers: differences that matter. J Hum Hypertens 2002; 16 (Suppl. 3): S9–S16. 5 The Expert Committeee on the diagnosis and classification of diabetes mellitus. Report of the Expert Committeee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 (Suppl. 1): 5–20. 6 Fogari R et al. Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hyperten-

sive type 2 diabetic patients. Am J Hypertens 2002; 15: 316–320. Bonora E et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. 2000; 23: 57–63. Trenkwalder P, Lehtovirta M, Dahl K. Long-term treatment with candesartan cilexetil does not affect glucose homeostasis or serum lipid profile in mild hypertensives with type II diabetes. J Hum Hypertens 1997; 11 (Suppl. 2): S81–S83. Higashiura K, Ura N, Miyazaki Y, Shimamoto K. Effect of an angiotensin II receptor antagonist, candesartan, on insulin resistance and pressor mechanisms in essential hypertension. J Hum Hypertens 1999; 13 (Suppl. 1): S71–S74. Derosa G et al. Effects of fosinopril on blood pressure, lipid profile, and lipoprotein (a) levels in normotensive patients with type 2 diabetes and microalbuminuria: an open-label, uncontrolled study. Curr Ther Res Clin Exp 2002; 63: 216–226.

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G Derosa, AFG Cicero, A Mugellini, L Ciccarelli and R Fogari Department of Internal Medicine and Therapeutics University of Pavia, Pavia, Italy Department of Clinical Medicine and Applied Biotechnolgy ‘D Campanacci’, University of Bologna, Bologna Italy Correspondence: G Derosa Dr G Derosa Department of Internal Medicine and Therapeutics University of Pavia, P le C Golgi, 2, 27100 Pavia Italy E-mail: [email protected]

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