Effectiveness and metabolic effects of perindopril and ... - Nature

Journal of Human Hypertension (1999) 13, 787–791  1999 Stockton Press. All rights reserved 0950-9240/99 $15.00 http://www.stockton-press.co.uk/jhh

ORIGINAL ARTICLE

Effectiveness and metabolic effects of perindopril and diuretics combination in primary hypertension MS Elisaf, J Theodorou, H Pappas, N Papagalanis, K Katopodis, R Kalaitzidis and KC Siamopoulos Department of Internal Medicine, University of Ioannina Medical School, Greece

The effectiveness as well as the metabolic effects of the combination of diuretics [hydrochlorothiazide (HCT) vs indapamide (IND)] and perindopril (P) in 14 patients (7 male, 7 female) aged 37–62 years with mild idiopathic hypertension were studied. Following a 4-week washout period and a 4-week period of monotherapy with P (4 mg/daily), IND (2.5 mg/daily) or HCT (25 mg/daily) was added for 4 weeks. Selection of the diuretic agent was random. Following a 4-week wash-out period from the diuretic, in which only P was given, the alternative diuretic was administered for another period of 4 weeks. P decreased blood pressure levels significantly. However, the drug was more efficacious in patients with higher plasma renin activity (PRA). Combination treatment induced an additional decrease in the blood pressure levels, mainly in patients with lower PRA. The combination of P ⴙ HCT was more effective than the combination P ⴙ IND. The addition of either HCT or IND

evoked a small but statistically significant increase in serum glucose levels while fasting as well as during the 75 g oral glucose challenge. However, insulin levels did not change significantly during the study. Small but not statistically significant changes in serum electrolytes and lipid parameters were observed during the various phases of the study, while a statistically significant increase in the serum uric acid was noticed when the combination P ⴙ HCT was given. We conclude: (1) P in small doses is an effective and safe antihypertensive agent, (2) PRA has a predictive value in determining the effectiveness of P treatment, (3) the combination of P with small doses of HCT or IND is more efficacious than P alone, (4) the combination treatment has adverse effects in the carbohydrate tolerance, while there are not significant changes in serum electrolyte and lipid parameters.

Keywords: perindopril; hydrochlorothiazide; indapamide; plasma renin activity; combination drug therapy for hypertension; metabolic effects of antihypertensive treatment

Introduction Angiotensin-converting enzyme (ACE) inhibitors comprise a class of antihypertensive drugs with a very low side-effect profile.1 However, single drug therapy is effective in approximately half of hypertensive patients. In the remaining patients, a synergistic effect upon hypotensive efficacy has been observed when even small doses of diuretics are added.2–5 Even though diuretics exert adverse metabolic effects, ACE inhibitors appear to exhibit a neutral or even a beneficial effect on lipid and carbohydrate metabolism, leading to an attenuation of the biochemical sequalae commonly associated with diuretic therapy.6–11 However, indapamide has been reported to induce a moderate change in the serum metabolic parameters.12,13 Therefore, we undertook the present study to examine the efficacy as well as the metabolic effects

Correspondence: Dr Moses S Elisaf, Associate Professor of Medicine, Department of Internal Medicine, University of Ioannina, Medical School, GR 451 10 Ioannina, Greece Received 10 January 1999; accepted 25 February 1999

of the combination of indapamide or hydrochlorothiazide with perindopril.

Materials and methods A total of 14 patients (7 male, 7 female) aged 37–62 years with mild to moderate primary hypertension (sitting diastolic blood pressure (BP) ⭓95 mm Hg and ⭐114 mm Hg) were studied. All patients had been previously identified by the investigators as requiring a drug combination to control their BP. Criteria for exclusion were significant cardiac, hepatic, renal, and thyroid diseases, diabetes mellitus, and weight in excess of 20% of ideal body weight. Patients were not given any advice on their eating, smoking, or exercise habits during the study. Administration of any previous antihypertensive medication was discontinued at least 4 weeks before the study. The study protocol was approved by the Hospital Ethics Committee and each patient gave written consent to participate in the study. Study protocol is shown in Figure 1. Specifically, after the 4 weeks’ wash-out period, all patients were given perindropril (4 mg once daily) for 4 weeks. Taking into account that the seated diastolic BP after

Combination therapy with perindopril and diuretics MS Elisaf et al

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Figure 1 Study protocol. P: perindopril (4 mg/daily), HCT: hydrochlorothiazide (25 mg/daily), IND: indapamide (2.5 mg/daily).

perindopril treatment was more than 90 mm Hg, indapamide (2.5 mg once daily) or hydrochlorothiazide (25 mg once daily) was added for 4 weeks. Selection of the diuretic agent was random. Following a 4-week wash-out period from the diuretic, in which only perindopril was given, the alternative diuretic was administered for another period of 4 weeks. At every visit (every 4 weeks) each patient’s BP was measured in the right arm with a standard mercury sphygmomanometer after the patient remained seated for 10 min. Additionally, heart rate and body weight were also measured. Compliance with drug treatment was assessed in each patient by an interview and a pill count. In all study periods venous blood was obtained after a 12 h fast for the determination of serum metabolic parameters (glucose, creatinine, uric acid, sodium, potassium, magnesium, total cholesterol, high-density lipoprotein (HDL) cholesterol, lowdensity lipoprotein (LDL) cholesterol, apolipoprotein A1, apolipoprotein B, and triglycerides). At the same time, glucose tolerance tests after ingestion of 75 g of glucose was performed and samples for serum glucose and insulin were drawn at 0, and 2 h. In all patients plasma renin activity (PRA) was measured at the beginning of the study along with 24-h urine sodium excretion. Serum creatinine was measured by the method of Jaffe, serum glucose by the hexokinase method, serum sodium and potassium by ion selective electrodes, serum magnesium by photometric colorimetric assay, serum uric acid by the uricase/PAP method, and serum insulin by the Abbott IMx insulin assay, which is a microparticle enzyme immunoassay. Serum cholesterol and triglycerides were determined by enzymatic colorimetric assay using an RA1000 analyser (Technicon Instruments, NY, USA), while HDL cholesterol was determined enzymatically in the supernatant after precipitation of other lipoproteins with dextran sulfate-magnesium. LDL cholesterol was calculated using the Friedewald formula. Serum Apo A1 and ApoB were measured by immunonephelometry with the aid of a Beckman array analyser (Beckman Instruments, CA, USA). PRA was measured by a radioimmunoassay. Statistical analysis Data are presented as means ± standard deviation. Blood pressure and biochemical parameters at the

end of each study period were used for statistical analysis according to that recommended by Hills and Armitage.14 This method allows comparison of the effects of combination of perindopril either with hydrochlorothiazide or with indapamide to be adjusted for any period effects. This method also includes a test for treatment-period interaction. Comparison of the effects of perindopril used either alone or in combination with diuretics was derived from the differences among responses for the study periods. Significance was assessed with Student’s tstatistic. No carryover effect was detected for any variable measured and therefore there was no necessity to analyse any variables as a parallel study. All statistical tests were two-tailed and were interpreted at the 5% significance level.

Results A significant decrease in the mean BP was observed after perindopril administration in the whole group of patients [from 118.9 ± 9.3 to 108.9 ± 7.9 mm Hg, mean reduction of 8.4%, P ⬍ 0.005]. Perindopril was more efficacious in patients with higher PRA, since patients with a more than 5 mm Hg decrease in mean BP (range, 5.8–10.6 mm Hg) had higher PRA compared to those with a decrease in mean BP less than 5 mm Hg (range, 0.4 –4.2 mm Hg) [2 ± 0.8 ng/ml/h vs 0.4 ± 0.5 ng/ml/h, P ⬍ 0.01]. Furthermore, there was a good correlation between PRA values and the decrease in mean BP (r = 0.42, P = 0.02). The addition of either hydrochlorothiazide or indapamide produced an additional decrease in mean BP from 108.2 ± 8 mm Hg on monotherapy to 87 ± 9 mm Hg after 4 weeks’ treatment with hydrochlorothiazide (mean reduction of 14%, P ⬍ 0.005) and from 109 ± 6.8 mm Hg on monotherapy to 98.5 ± 7 mm Hg after 4 weeks’ treatment with indapamide (mean reduction of 9.6%, P ⬍ 0.01). However, the perindopril + hydrochlorothiazide combination was more effective than the perindopril + indapamide combination (P ⬍ 0.05). No significant changes in serum lipid parameters were observed after perindopril administration in the whole group of patients (mean changes of all lipid parameters ⬍ 5%, P = NS). As shown in Table 1, both diuretics increased the total and LDL cholesterol levels moderately, though not significantly. However, there were no significant differences in the changes of all lipid parameters measured


Table 1 Mean changes (%) in serum lipid parameters after diuretics administration Parameters (mg/dl) Total cholesterol HDL cholesterol LDL cholesterol Triglycerides Apolipoprotein A1 Apolipoprotein B

After HCT (%)

After IND (%)

Pa

9.5 −1.2 8.5 6.0 −3.0 9.0

7 −1 7 5 −2 6

NS NS NS NS NS NS

a

P between the two combination therapies, HCT: hydrochlorothiazide, IND: indapamide.

between the two combination therapies. Perindopril administration was followed by an increase in serum potassium levels (from 4.1 ± 0.2 mm Hg to 4.3 ± 0.3 mm Hg, P = 0.08). Both hydrochlorothiazide and indapamide produced a decrease in serum potassium levels to lower than pretreatment values (from 4.4 ± 0.2 mmol/L to 3.95 ± 0.2 mmol/L after hydrochlorothiazide treatment, and from 4.3 ± 0.15 mmol/L to 4 ± 0.2 mmol/L after indapamide treatment), even though the changes in serum potassium levels were only marginally statistically significant (P = 0.08 for hydrochlorothiazide and P = 0.09 for indapamide) possibly because of the relatively small number of patients studied. An approximately 10% decrease in serum magnesium levels was found after both diuretics’ administration. However, there were no significant differences in the changes of serum electrolytes between the two combination therapies (Table 2). A significant increase in serum uric acid levels was observed after hydrochlorothiazide administration (from 5.2 ± 1.3 mg/dl to 6 ± 1.4 mg/dl, P ⬍ 0.01), while indapamide did produce a small insignificant increase in uric acid levels (from 5.3 ± 0.9 mg/dl to 5.7 ± 0.8 mg/dl, P = NS). Subsequently, the addition of hydrochlorothiazide caused a greater increase in serum uric acid levels compared to that observed after indapamide administration (P ⬍ 0.01). Perindopril treatment was not followed by any change in either fasting or 2 h postload serum glucose levels (from 96 ± 12 mg/dl to 91 ± 9 mg/dl, and from 120 ± 12 mg/dl to 118 ± 24 mg/dl, respectively) and insulin levels (from 10.2 ± 3 mU/L to 9.9 ± 4 mU/L and from 13 ± 3 mU/L to 12 ± 6 mU/L, respectively). Both diuretics increased significantly fasting and 2 h Table 2 Mean changes (%) in serum metabolic parameters after diuretics administration Serum parameters

Potassium (mmol/L) Sodium (mmol/L) Magnesium (mmol/L) Creatinine (mg/dl) Uric acid (mg/dl) a

After HCT After IND administration administration (%) (%) −10.5 −2.0 −9.0 7.0 15.5*

−8.4 −1.5 −8.0 5.0 7.5

postload glucose levels (from 90 ± 11 mg/dl to 103 ± 9 mg/dl, P ⬍ 0.01 and from 115 ± 16 mg/dl to 132 ± 12 mg/dl, P ⬍ 0.01, respectively after hydrochlorothiazide administration and from 89 ± 14 mg/dl to 99 ± 12 mg/dl, P ⬍ 0.01, and from 119 ± 16 mg/dl to 132 ± 12 mg/dl, P ⬍ 0.01, respectively after indapamide administration), while there were no significant differences in the changes of carbohydrate metabolism parameters between the two combination therapies. Even though the fasting and 2 h postload serum insulin levels were somewhat increased after the addition of both diuretics, the changes were not statistically significant (Table 3).

Discussion Our study reconfirmed that perindopril is an effective antihypertensive drug without any adverse metabolic effects on carbohydrate or lipid metabolism.15 In agreement with previously published data the drug’s antihypertensive efficacy was related to the renin-angiotensin axis activation; that is, the BP fall was well correlated to the pretreatment PRA.16,17 However, a considerable proportion of hypertensive patients exhibit an inadequate response to monotherapy with ACE inhibitors, as was the case in our patients.3,18 In such cases, the addition of a diuretic to a standard dose of ACE inhibitor gives a better response than increasing the dose of ACE inhibitor.4 Thus, the combination of ACE inhibitors with diuretics appears to represent an ideal choice in terms of efficacy, compliance, side effects and cost.19–21 In fact, in our patients a near normalisation of BP values after diuretics administration was achieved. The synergistic action of ACE inhibitordiuretic combination allows the diuretic dose to be reduced, leading to a reduction in the metabolic side effects commonly observed with diuretic therapy.8,22,23 Accordingly, previous studies have shown that the addition of ACE inhibitors to thiazides can blunt or even prevent the metabolic consequences of diuretic therapy, while they enhance their antihypertensive effect.6–11 Nonetheless, there seem to be a few studies concerning the metabolic consequences of added thiazide diuretics to ACE inhibitors. Additionally, comparison of the observed biochemical derangements between hydrochlorothiazide and indapamide when added to ACE inhibitors is lacking. This is of special importance, since indapamide is an effective and safe antihyperTable 3 Mean changes (%) of carbohydrate metabolism parameters after diuretics administration

Pa Parameters

NS NS NS NS 0.05

P between the two combination therapies. *P ⬍ 0.01 compared to values obtained during P treatment. HCT: hydrochlorothiazide, IND: indapamide, P: perindopril.

Fasting glucose (mg/dl) 2 h glucose (mg/dl) Fasting insulin (mU/L) 2 h insulin (mU/L) a

After HCT After IND administration administration (%) (%) 14* 14.5* 11 7

11* 10.5* 9 6

Pa

NS NS NS NS

Between the two combination therapies. *P ⬍ 0.01 compared to values obtained during P treatment. HCT: hydrochlorothiazide, IND: indapamide, P: perindopril.

789


790

tensive drug, thought to be unique among diuretics devoid of lipid or other metabolic effects.12,13 However, our study showed that hydrochlorothiazide at a dose of 25 mg/day was more effective than indapamide at a dose of 2.5 mg/day, when both drugs are added in patients on perindopril treatment. Thus, our results point to the suggestion that a hydrochlorothiazide dose of not less than 25 mg is necessitated to achieve optimal BP lowering.7,9 Nevertheless, at this dosage a number of adverse metabolic effects was observed, namely a 10% increase in serum total and LDL cholesterol levels, an increase in serum uric acid levels, and, most importantly, a significant increase in serum glucose levels. Similar changes, however, even though of lower degree, were also found after indapamide treatment, while the only significant difference between the two combination therapies concerns the increase in serum uric acid levels, which was significantly higher after hydrochlorothiazide administration. Interestingly, after both diuretics’ treatment a significant increase in fasting and 2 h postload glucose levels was evident, while no significant change in both fasting and 2 h postload insulin levels was found, suggesting that diuretics could directly or indirectly (through hypokalaemia) decrease pancreatic insulin secretion.24,25 Even though evaluation of insulin sensitivity using the euglycaemic glucose clamp technique was not performed in our study, it is noteworthy that no beneficial effect of perindopril on serum glucose and insulin levels both fasting and 2 h postloading relative to baseline was demonstrated. Thus, the putative beneficial effect of ACE inhibitors on carbohydrate metabolism remains controversial.26–29 It is possible that the impact on sensitivity to insulin varies with different ACE inhibitors,30 and it is dependent on the degree of underlying insulin resistance. If subjects are not particularly insulin resistant, as was the case in our patients, then it may be more difficult to reveal a beneficial effect.26 Furthermore, the ACE inhibitor dosage could have also played a role in its influence in the carbohydrate tolerance, since in one study the administration of only high doses of captopril (⬎100 mg/day) mitigated the hyperglycaemic effect of hydrochlorothiazide.6 Therefore, a placebo-controlled study to address the effect of ACE inhibition on sensitivity to insulin in essential hypertension needs to be carried out. A small increase in serum potassium levels was observed after perindopril therapy and a decrease to lower than pretreatment values followed the two combination therapies. Nevertheless, the 25 mg of hydrochlorothiazide did not induce a significant decrease in serum potassium levels to hypokalaemic levels, suggesting that perindopril guards against the hypokalaemic effects of the added diuretics. The changes in potassium homeostasis could have played a role in the diuretic-induced adverse effects on carbohydrate metabolism. It has been suggested that the decrease in serum potassium levels might impair insulin secretion and inhibit muscle glucogen synthase activity, which is associated with a decrease in insulin-mediated uptake of glucose.24,31 Our data clearly showed that the administration

of ACE inhibitor did not ameliorate the adverse effects of diuretics in agreement with recently published data, which reported that combination therapy evoked hepatic insulin resistance when 5 mg of bendrofluazide was used.26 Consequently, great care needs to be exercised in the use of these combinations notwithstanding that they are particularly efficacious in lowering BP, as it is also illustrated in the present study. It should be mentioned that it is not certain what the effects of ACE inhibitors combined with lower doses of hydrochlorothiazide will be. This is of special importance, since many of the combined proprietary preparations of ACE inhibitors and thiazides available in Europe contain smaller quantities of thiazide diuretics compared to those used in this study.

References 1 Berne C. Metabolic effects of ACE inhibitors. J Intern Med 1991; 229 (Suppl 2): 119–125. 2 Townsend RR, Bryan Holland O. Combination of converting enzyme inhibitor with diuretic for the treatment of hypertension. Arch Intern Med 1990; 150: 1175–1183. 3 McAreavey D et al. ‘Third Drug’ trial: comparative study of antihypertensive agents added to treatment when blood pressure remains uncontrolled by a betablocker plus thiazide diuretic. Br Med J 1984; 288: 106–110. 4 Sassano P et al. Comparison of increase in the enalapril dose and addition of hydrochlorothiazide as second-step treatment of hypertensive patients not controlled by enalapril alone. J Cardiovasc Pharmacol 1989; 13: 314 –319. 5 Weinberger MH. Comparison of captopril and hydrochlorothiazide alone and in combination in mild to moderate essential hypertension. Br J Clin Pharmacol 1982; 14: 127S–131S. 6 Weinberger MH. Influence of an angiotensin converting-enzyme inhibitor on diuretic-induced metabolic effects in hypertension. J Hypertens 1983; 5 (Suppl 3): 132–138. 7 Scholze J, Group for the East Germany Collaborative Trial. Short report: ramipril and hydrochlorothiazide combination therapy in hypertension: a clinical trial of factorial design. J Hypertens 1993; 11: 217–221. 8 Chrysant SG, The Lisinopril–Hydrochlorothiazide Group. Antihypertensive effectiveness of low-dose hydrochlorothiazide combination. A large multicenter study. Arch Intern Med 1994; 154: 737–743. 9 Canter D et al. Quinapril and hydrochlorothiazide combination for control of hypertension: assessment by factorial design. J Hum Hypertens 1994; 8: 155–162. 10 Lacourcie`re Y, Gagne` C. Influence of combination of captopril and hydrochlorothiazide on plasma lipids, lipoproteins and apolipoproteins in primary hypertension. J Hum Hypertens 1993; 7: 149–152. 11 Weinberger MH. Influence of an angiotensin-converting enzyme inhibitor on diuretic-induced metabolic effects in hypertension. Hypertension 1983; 5: 132–138. 12 Osei K, Holland G, Falko M. Indapamide. Effects on apoprotein, lipoprotein, and glucoregulation in ambulatory diabetic patients. Arch Intern Med 1986; 146: 1973–1977. 13 Campbell DB, Moore RA. The pharmacology and clinical pharmacology of indapamide. Postgrad Med J 1981; 57 (Suppl 2): 7–17


14 Hills M, Armitage P. The two-tailed cross-over trial. Br J Clin Pharmacol 1979; 8: 7–10. 15 Lees KR et al. Captopril versus perindopril: a doubleblind study in essential hypertension. J Hum Hypertens 1989; 3: 17–22. 16 Case DB et al. Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme. N Engl J Med 1977; 296: 641– 646. 17 MacGregor GA et al. Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol. Br Med J 1982; 284: 693–696. 18 Veterans Administration Cooperative Study Group on Antihypertensive Agents. Captopril: evaluation of low doses, twice-daily doses and the addition of diuretic for the treatment of mild to moderate hypertension. Clin Sci 1982; 63 (Suppl 8): 443S– 445S. 19 Holland OB, Kuhnert LV, Campbell WB, Anderson RJ. Synergistic effect of captopril with hydrochlorothiazide for the treatment of low-renin hypertensive black patients. Hypertension 1983; 5: 235–239. 20 Atkinson AB, Brown JJ, Lever AF, Robertson JIS. Combined treatment of severe intractable hypertension with captopril and diuretic. Lancet 1980; ii: 105–108. 21 Weinberger MH. Blood pressure and metabolic responses to hydrochlorothiazide, captopril, and the combination in black and white mild-to-moderate hypertensive patients. J Cardiovasc Pharmacol 1985; 7: S52–S55. 22 Dahlo¨f B et al. Potentiation of the antihypertensive effect of enalapril by randomised addition of different doses of hydrochlorothiazide. J Hypertens 1985; 3: S483–S486. 23 Andren L, Weiner L, Svensson A, Hanson L. Enalapril with either a “very low” or “low” dose of hydrochloro-

24 25

26

27

28 29

30

31

thiazide is equally effective in essential hypertension. A double-blind trial in 100 hypertensive patients. J Hypertens 1983; 1: 384 –386. Fajan SS et al. Benzothiazidine suppression of insulin release from normal and abnormal islet cell tissue in man. J Clin Invest 1966; 45: 481– 493. Santoro D et al. Effect of chronic angiotensin-converting enzyme inhibition on glucose tolerance and insulin sensitivity in essential hypertension. Hypertension 1992; 20: 181–191. Hunter SJ et al. Effects of combination therapy with an angiotensin converting enzyme inhibitor and thiazide diuretic on insulin action in essential hypertension. J Hypertens 1998; 16: 103–109. Pollare T, Lithell H, Selinus I, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989; 321: 868–873. Seghieri G et al. Effect of chronic ACE inhibition on glucose tolerance and insulin sensitivity in hypertensive type 2 diabetics. Diabetic Med 1992; 9: 732–738. Prince MJ et al. Metabolic effects of hydrochlorothiazide and enalapril during treatment of the hypertensive diabetic patient. Arch Intern Med 1988; 148: 2363– 2368. Uehara M et al. Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans. Diabetologia 1994; 37: 300–307. Bogardus C, Lillioja S, Stone K, Mott D. Relationship between muscle glycogen synthase activity on in vivo insulin action in man. J Clin Invest 1984; 73: 1185– 1190.

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