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Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension
Diabetes Research and Clinical Practice 71 (2006) 210–219 www.elsevier.com/locate/diabres
Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension Ahmet M. Sengul *, Yu¨ksel Altuntas, Akın Ku¨rklu¨, Levent Aydın Department of 2nd Internal Medicine, Division of Endocrinology and Diabetes, Sisli Etfal Education and Research Hospital, Istanbul, Turkey Received 14 December 2004; received in revised form 12 April 2005; accepted 23 June 2005 Available online 19 August 2005
Abstract Angiotensin-converting enzyme (ACE) inhibitors have favourable effects on hypertension and diabetic nephropathy, but persistent use may result in incomplete blockade of the renin–angiotensin system. Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker (ARB) telmisartan on blood pressure and albumin excretion rate (AER) were evaluated. Patients with type 2 diabetes mellitus, hypertension (systolic blood pressure [SBP] 140 mmHg or diastolic blood pressure [DBP] 90 mmHg) and microalbuminuria (AER 30–300 mg/24 h) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks. Patients were then randomised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks. Significant (P < 0.001) declines in SBP (11.1 mmHg versus 10.0 mmHg), DBP (5.6 mmHg versus 5.3 mmHg) and AER (98 mg/24 h versus 80 mg/24 h) were achieved with lisinopril (n = 95) or telmisartan (n = 97), respectively, after 24 weeks. Subsequent treatment with lisinopril plus telmisartan for 28 weeks resulted in further significant reductions (P < 0.001) in SBP, DBP and AER compared with either monotherapy. All treatments were well tolerated. Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy. We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes, hypertension and microalbuminuria. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetes mellitus; Hypertension; Microalbuminuria; Lisinopril; Telmisartan; Combination therapy
1. Introduction Diabetes is the most common cause of end-stage renal disease (ESRD) in the western world [1]. In the * Corresponding author. Tel.: +90 212 660 20 07; fax: +90 212 660 20 07. E-mail address: [email protected] (A.M. Sengul).
USA, diabetic nephropathy accounts for nearly 40% of new cases of ESRD, and 20–30% of patients with type 1 or type 2 diabetes develop overt nephropathy [2], characterised by persistent microalbuminuria, elevated blood pressure and a decline in the creatinine clearance, ultimately leading to ESRD [3]. Microalbuminuria, in addition to being the earliest manifestation of nephropathy, is a strong risk factor for
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.06.010
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all-cause and cardiovascular mortality in patients with either type 1 or 2 diabetes [4–6]. The benefits of angiotensin-converting enzyme (ACE) inhibitors in diabetic nephropathy are well documented [7–10], notably reducing the incidence of diabetic nephropathy in both hypertensive and normotensive type 1 or 2 diabetic patients with microalbuminuria [11]. In addition, they reduce the rate of mortality [12] and the need for dialysis or a kidney transplant in patients with type 1 diabetes and overt nephropathy [13]. ACE inhibitors are thought to act within the kidneys by reducing efferent arteriolar pressure, thereby decreasing intraglomerular pressure and reducing albumin excretion [14]. Furthermore, they act on the endothelium and decrease vascular smooth muscle growth, decrease release of endothelin, and increase fibrinolysis and release of vasodilatory substances, such as nitric oxide and prostacyclin, mediated by bradykinin [15]. Renoprotective effects of ACE inhibitors are a result of the suppressed generation of angiotensin II in both plasma and tissues. However, in many people, ACE inhibitor monotherapy fails to achieve blood pressure targets [16] and, in patients with chronic kidney disease, many progress to ESRD [17]. The unsatisfactory antihypertensive response may be explained by incomplete blockade of the renin–angiotensin system (RAS), the ‘ACE escape’ phenomenon [18] leading to the generation of angiotensin II by alternative ACEindependent pathways, such as chymase [19]. Angiotensin II receptor blockers (ARBs) also target the RAS, but lower blood pressure by preventing the binding of angiotensin II to type 1 (AT1) receptors. The ARBs appear to be as effective as ACE inhibitors in renoprotection [20,21]. The possibility of combining an ACE inhibitor with an ARB, rather than using a supramaximal dose of an ACE inhibitor, has been a matter of debate [22]. To date, benefits have been demonstrated in the short-term, but the results have not been consistent in all studies [23]. Furthermore, the longer-term advantages of administering an ACE inhibitor and an ARB have yet to be demonstrated. In this prospective, randomised study, we evaluated the long-term effect of dual blockade of the RAS using a combination of an ACE inhibitor (lisinopril) and an ARB (telmisartan) with a long terminal elimination half-life [24] and long duration of action [25,26], on blood pressure and the albumin excretion rate (AER)
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in diabetic, hypertensive patients with persistent microalbuminuria.
2. Materials and methods 2.1. Patient selection The study was conducted in 219 patients with type 2 diabetes based on World Health Organization criteria [27]. Patients were between 40- and 65year-old and had previously diagnosed hypertension (systolic blood pressure [SBP] 140 mmHg or diastolic blood pressure [DBP] 90 mmHg), despite receiving ACE inhibitor monotherapy for 6 months, and microalbuminuria (AER rate 30–300 mg/24 h for a minimum of three consecutive occasions). Exclusion criteria were type 1 diabetes, body mass index 40 kg/ m2, secondary diabetes, alcoholism, thyroid disease, SBP >200 mmHg, any non-diabetic cause of secondary hypertension (including bilateral renal artery stenosis), urinary tract infection, persistent haematuria, chronic liver disease, overt carcinoma, any cardiovascular event in the previous 6 months, serum creatinine 150 mmol/l, serum potassium 5.5 mmol/l or pregnancy. All patients were required to give informed consent to participate after the nature of the study had been explained. 2.2. Study design The randomised, parallel-group, open-label, crossover, prospective study was performed in accordance with the Helsinki Declaration, and with local Ethical Committee approval. There was an initial 2-week wash-out period before eligible patients were assigned to treatment of 20 mg of lisinopril (n = 110) or 80 mg of telmisartan (n = 109), administered after breakfast and before 09:00 a.m. once a day for 24 weeks (Fig. 1). After 24 weeks, half of the patients receiving lisinopril were randomised to receive 80 mg of telmisartan once a day in addition. Similarly, half the patients initially treated with telmisartan received a combination of 20 mg of lisinopril plus 80 mg of telmisartan. The remaining patients continued to be treated with monotherapy. Treatment was continued for a further 28 weeks. The treatment was individualised in both groups according to blood pressure throughout the
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SBP and DBP were measured in the morning about 24 h after the previous drug administration (trough value) using an automatic device (Omron HEM-705 CP, Omron Electronics, Tokyo, Japan) with the patient having been seated for 10 min. The mean of the three measurements taken at 5-min intervals was recorded. Blood pressure was also measured once after the patient had been standing for 2 min. Microalbuminuria was determined using turbidimetry (Cobas Mira Plus, Roche, Montclaire, NJ, USA) as the geometric mean of AER of three consecutive 24-h urine collections. The intra-assay and interassay coefficients of variation were 3.4 and 5.0%, respectively. Creatinine clearance was calculated with the Cockcroft–Gault formula: Fig. 1. Design of study to evaluate the effect of once-daily lisinopril 20 mg and/or telmisartan 80 mg on blood pressure and microalbuminuria in patients with type 2 diabetes.
study period with the addition of hydrochlorothiazide. Patients were instructed to follow a normocaloric diet (30 kcal/kg) with a sodium level of about 150 mmol/day and a constant amount of protein (1.2 g/kg). Lifestyle and diabetes treatment remained unchanged throughout the study. Patients were withdrawn if any of the following occurred: serum potassium >5 mmol/l, SBP 200 mmHg and/or DBP 60 mmHg and/or returned medication exceeded 5% of expected. 2.3. Measurements During the study, the patients attended a clinic on seven occasions: screening, randomisation after the 2-week wash-out, and 6, 12, 24, 36 and 52 weeks after the initial randomisation. Drug compliance was confirmed by a tablet count of returned medication. Blood samples were collected after an overnight fast of 12 h. Patients were also examined for retinopathy at each visit by the same ophthalmologist. At the screening visit, AER and seated blood pressure were measured, and serum potassium and creatinine were determined. At each subsequent visit, blood pressure, AER, plasma glucose, glycosylated haemoglobin (HbA1c), serum potassium, lipid profiles and creatinine clearance were determined.
140 age ðyearsÞ weight ðkgÞ K serum creatinine ðmmol=lÞ where K was 1.25 for men and 1.4 for women. HbA1c was measured by high-performance liquid chromatography using a commercial kit (Bio-Rad); reference levels were 4–6% and the interassay coefficient of variation was 3%. Serum triglycerides and cholesterol were determined by enzymatic colorimetric methods using kits (Boehringer Mannheim GmbH, Diagnostica, Mannheim, Germany). High-density lipoprotein cholesterol was measured by a precipitation-based method with phosphotungstic acid [28]. Low-density lipoprotein cholesterol was calculated using Friedewald’s formula [29]. Plasma glucose was determined by the glucose oxidase method (GOD-Perid, Boehringer Mannheim, Mannheim, Germany). Serum potassium, sodium, creatinine and cholesterol concentrations were assayed using a BM-Hitachi system (Boehringer Mannheim GmbH, Roche Laboratory Systems, Mannheim, Germany). Tolerability was assessed at each visit by spontaneously reported adverse events recorded in response to an open question or observed by the investigator. 2.4. Statistical analysis Data were analysed using SPSS version 11.0 (SPSS, Chicago, IL, USA). Normally distributed variables were expressed as mean S.D. and otherwise as median (range). Changes in variables between visits were expressed as the mean values together with
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95% confidence intervals (CI). Differences in AER within the groups were compared using Student’s t-test, and differences between the groups regarding the change in UAE were compared using ANOVA. For all treatment groups, the changes in arterial blood pressure and creatinine clearance from baseline to 24 and 52 weeks were analysed using a linear model for analysis of covariance (ANCOVA), with treatment, interaction between treatments and baseline value as covariates. For AER, ANCOVA was used with changes in SBP, DBP and body weight used as covariates. Linear regression analysis was employed to establish any correlation between changes in blood pressure and relative change in GFR. Spearman‘s rank correlation coefficient was employed to determine the correlation between the change in blood pressure and the change in microalbuminuria. A P-value of < 0.05 was considered statistically significant (two-sided test).
3. Results 3.1. Patient baseline characteristics Baseline characteristics of the 219 enrolled patients are summarised in Table 1. There were no statistically
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significant differences between the two groups with respect to age, body mass index, plasma lipid profiles, duration of diabetes mellitus, HbA1c, serum creatinine, blood pressure and smoking habits. Seventy-six patients assigned to telmisartan treatment and 77 patients assigned to lisinopril were taking oral antidiabetic drugs; the remainder (33 patients in each group) were being treated with insulin. The antidiabetic treatment regimens remained relatively constant throughout the study period. In addition, 12.5 mg of hydrochlorothiazide once a day was used to treat 19 patients in the telmisartan group and 21 in the lisinopril group. In total, 27 patients were excluded from the study: 15 on lisinopril due to discontinuation of the study protocol or side-effects of the drug such as nausea, stomach upset, respiratory infection, cough, headache, dizziness or feeling weak and 12 on telmisartan due to nausea, headache, dizziness, stomach upset, cough, gastrointestinal problems and withdrawal of consent. Retinopathy was present in 72 patients randomized to telmisartan and 73 who were receiving lisinopril, but it was not proliferative. There were no differences in the prevalence of neuropathy and other macroangiopathic complications between the groups at baseline and during the 52-week study.
Table 1 Baseline characteristics of patients with hypertension, microalbuminuria and type 2 diabetes followed from baseline to 24 weeks of monotherapy Telmisartan (n = 109)
Lisinopril (n = 110)
Sex (female/male) Age (years) Body mass index (kg/m2) Duration of diabetes (years) Smokers, n (%) SBP (mmHg) DBP (mmHg)
69/40 56.5 8.2 30.6 4.2 11.7 7.1 39 (35.8) 150.4 14.2 89.9 5.4
68/42 56.7 8.3 30.1 3.9 11.8 7.0 41 (37.3) 151.2 14.4 87.9 5.2
AER (mg/24 h) Median Range
256 140–300
264 150–300
Serum creatinine (mmol/l) Creatinine clearance (ml/min) HbA1c (%) Serum potassium (mmol/l) Total cholesterol (mg/dl) LDL cholesterol (mmol/l) Triglycerides (mmol/l)
85.6 18.4 97.2 20.1 7.9 1.4 4.2 0.4 5.2 2.3 3.36 1.4 2.2 1.0
85.4 17.4 96.4 20.0 7.8 1.2 4.3 0.4 5.7 2.4 3.6 1.6 2.1 0.9
SBP, systolic blood pressure; DBP, diastolic blood pressure; AER, urinary albumin excretion rate; HbA1c, glycosylated haemoglobin; LDL, lowdensity lipoprotein. Values are mean S.D. unless stated otherwise.
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Table 2 Adjusted reductions (95% confidence intervals [CI]) in blood pressure and urinary albumin excretion rate (AER) from baseline to 24 weeks of monotherapy Telmisartan
Lisinopril
Adjusted mean difference between treatmentsa
95% CI
P-value
SBP (mmHg) Mean Range P vs. baseline
10.0 7.1–14.5 <0.001
11.1 9.3–16.7 <0.001
1.1
1.1, 3.3
>0.2
DBP (mmHg) Mean Range P vs. baseline
5.3 3.1–8.2 <0.001
5.6 3.6–9.1 <0.001
0.3
1.0, 2.1
>0.2
AER (mg/24 h) Mean Range P vs. baseline
80 74–105 <0.001
98 80–124 <0.001
18
0, 37
0.12b
SBP, systolic blood pressure; DBP, diastolic blood pressure. a Adjusted for treatment, baseline value, weight and change in DBP. b Relative reduction.
3.2. Efficacy SBP and DBP fell significantly from baseline (P < 0.001 for both monotherapies; Table 2); there was no statistically significant difference between treatments (P > 0.05). Significant declines from baseline in AER were observed at 24 weeks (Table 2), decreasing by 31.3% from a median of 256 mg/24 h
(range 140–300 mg/24 h) to 176 mg/24 h (range 80– 220 mg/24 h) (P < 0.001) with telmisartan and by 37.1% from a median of 264 mg/24 h (range 150– 300 mg/24 h) to 166 mg/24 h (range 90–220 mg/24 h) with lisinopril (P < 0.001). The difference between treatments was not significant (P > 0.05). Table 3 shows the characteristics of the four groups at week 24 followed to week 52. Patients who were
Table 3 Characteristics of patients followed from 24 to 52 weeks Telmisartan (n = 48)
Lisinopril (n = 48)
Telmisartan + lisinopril (n = 49)
Lisinopril + telmisartan (n = 47)
Sex (female/male) Age (years) BMI (kg/m2) Duration of diabetes (years) SBP (mmHg) DBP (mmHg)
30/18 56.4 8.0 30.4 4.0 11.6 7.0 140.4 14.0 84.6 7.0
31/17 57.2 8.0 30.2 3.9 11.0 7.8 140.1 13.2 82.3 6.6
29/20 56.9 8.2 30.9 4.1 11.1 6.8 140.2 13.4 83.4 6.7
29/18 57.0 8.3 31.0 4.2 11.3 6.7 139.5 13.0 82.0 6.5
AER (mg/24 h) Median Range
176 80–220
166 90–220
174 55–212
175 45–205
Serum creatinine (mmol/l) Serum potassium (mmol/l) Creatinine clearance (ml/min) HbA1c (%) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mmol/l)
86.2 18.2 4.2 0.4 94.2 19.4 7.9 1.4 5.5 2.1 3.5 1.1 2.4 1.0
84.4 17.2 4.5 0.4 96.2 20.1 7.6 1.2 5.5 2.2 3.4 1.2 2.4 1.1
85.2 17.9 4.3 0.4 93.2 18.4 7.3 1.3 5.4 2.1 3.5 1.2 2.3 1.0
82.2 19.2 4.4 0.4 94.1 19.2 7.5 1.4 5.6 2.0 3.6 1.2 2.5 1.1
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AER, urinary albumin excretion; HbA1c, glycosylated haemoglobin. All figures are mean S.D., unless stated otherwise.
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founders, including gender, HbA1c, lipids, diabetes treatment, baseline values, body mass index, weight, age, duration of diabetes, smoking, serum creatinine, creatinine clearance and serum potassium. In the groups of patients who received the combination therapy, there was a measurable further reduction in AER (P < 0.001; Table 6). From baseline to week 52, percentage reductions in AER with telmisartan, lisinopril, telmisartan plus lisinopril and lisinopril plus telmisartan were 36.0, 40.5, 52.7 and 53.6%, respectively. AER was reduced to within the normal range (<30 mg/24 h) in eight patients in the lisinopril plus telmisartan group and in seven patients in the telmisartan plus lisinopril group at 52 weeks. On the other hand, AER was not reduced within the normal range in either monotherapy group at 24 or 52 weeks.
withdrawn from the study up until the 24-week visit were not included in the 52-week evaluation. After 52 weeks’ active treatment, data were available for 48 patients treated with telmisartan, 48 treated with lisinopril, 49 treated with telmisartan plus lisinopril and 47 treated with lisinopril plus telmisartan. Some patients in each treatment group also received 12–5 mg of hydrochlorothiazide once a day to achieve superior reductions in blood pressure: telmisartan (n = 9), lisinopril (n = 10), telmisartan plus lisinopril (n = 7), lisinopril plus telmisartan (n = 8). All treatments reduced AER (Table 4) and blood pressure (Table 5) at 52 weeks compared with baseline, with the combination being more effective than either monotherapy. The declines in both AER and blood pressure were independent of any con-
Table 4 The baseline and follow-up median (range) urinary albumin excretion rates (AER), serum creatinine, creatinine clearance and serum lipids
AER (mg/24 h) Baseline 12 weeks 24 weeks 36 weeks 52 weeks
Telmisartan
Lisinopril
Telmisartan + lisinopril
Lisinopril + telmisartan
P-value
256 216 176 170 164
264 224 166 160 157
258 – 174 139 122
259 – 175 140 120
0.431 0.321 0.436 <0.001 <0.001
*
(140–300) (80–245) (80–220) (57–214) (36–190)
(150–300) (100–270) (90–220) (46–200) (34–182)
(132–294) (75–212) (50–174) (23–172)
Serum creatinine (mmol/l) Baseline 85 (80–90) 12 weeks 84 (80–90) 24 weeks 86 (80–91) 36 weeks 85 (81–90) 52 weeks 82 (79–91)
86 85 84 86 83
Creatinine clearance (ml/min) Baseline 97.1 (90–100) 12 weeks 96.4 (89–99) 24 weeks 94.2 (80–98) 36 weeks 93.3 (88–96) 52 weeks 94.1 (90–98)
96.2 94.2 95.5 94.3 95.3
LDL cholesterol (mg/dl) Baseline 3.4 (1.4–4.5) 12 weeks 3.3 (1.3–4.3) 24 weeks 3.5 (1.6–4.6) 36 weeks 3.4 (1.2–4.5) 52 weeks 3.6 (1.4–4.8)
3.3 3.4 3.4 3.6 3.5
(1.3–4.4) (1.2–4.4) (1.5–4.7) (1.6–4.8) (1.5–4.6)
3.5 – 3.5 3.6 3.5
(1.4–4.5)
Triglycerides (mmol/L) Baseline 2.2 (1.0–3.2) 12 weeks 2.5 (1.1–3.5) 24 weeks 2.4 (1.3–3.6) 36 weeks 2.3 (1.2–3.5) 52 weeks 2.4 (1.3–3.6)
2.4 2.2 2.4 2.3 2.4
(1.1–3.2) (1.1–3.2) (1.2–3.6) (1.3–3.4) (1.2–3.5)
2.3 – 2.3 2.4 2.5
(1.2–3.4)
*
(80–90) (81–90) (82–91) (81–91) (80–92) (90–100) (88–98) (81–99) (88–96) (89–97)
p < 0.001 for both 36 and 52 weeks of treatment.
84 – 85 84 84
(79–90) (79–91) (80–90) (80–90)
95.3 – 93.4 95.3 94.4
(89–99) (88–98) (89–97) (88–98)
(1.5–4.8) (1.3–4.6) (1.4–4.7)
(1.4–3.5) (1.2–3.5) (1.4–3.6)
83 – 87 83 83
(141–292) (78–205) (40–170) (22–151)
(80–90) (81–90) (80–92) (79–91)
94.2 – 95.4 96.5 95.4
(89–100) (88–98) (90–98) (89–97)
3.5 – 3.6 3.5 3.4
(1.3–4.4)
2.2 – 2.5 2.4 2.4
(1.1–3.3)
(1.5–4.8) (1.4–4.5) (1.5–4.8)
(1.2–3.6) (1.3–3.7) (1.3–3.5)
0.412 0.422 0.436 0.322 0.345 0.420 0.329 0.336 0.401 0.388 0.424 0.329 0.430 0.396 0.404 0.429 0.367 0.466 0.349 0.398
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Table 5 Adjusted mean reduction and 95% confidence intervals (CI) in seated systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 52 weeks Telmisartan
Lisinopril
Telmisartan + lisinopril
Lisinopril + telmisartan
Mean
95% CI
Mean
95% CI
Mean
95% CI
Mean
95% CI
P-value (between treatment groups)
SBP (mmHg)
15.1 P < 0.001
9.1, 19.3
16.4 P < 0.001
11.1, 19.3
25.5 P < 0.001
16.0, 30.0
25.2 P < 0.001
16.7, 29.8
0.003
DBP (mmHg)
10.2 P < 0.001
7.1, 12.1
10.4 P < 0.001
7.8, 13.1
15.4 P < 0.001
12.6, 17.8
15.2 P < 0.001
12.4, 17.4
0.003
Table 6 Adjusted mean (95% confidence intervals [CI]) reduction in urinary albumin excretion rate (AER) from baseline to 52 weeks Telmisartan
AER (mg/24 h)
Lisinopril
Telmisartan + lisinopril
Mean
95% CI
Mean
95% CI
Mean
95% CI
Mean
95% CI
P-value (between treatment groups)
92 P < 0.001
42, 124
107 P < 0.001
34, 148
136 P < 0.001
24, 172
139 P < 0.001
23, 181
0.04
None of the patients receiving either monotherapy or combination therapy developed macroalbuminuria (AER >300 mg/24 h). 3.3. Tolerability and safety All treatment regimens were well tolerated. The most frequent adverse events were coughing, occurring exclusively in patients receiving lisinopril, and headache, which were experienced by less than 10% of the patients. There were no significant changes in mean values for HbA1c or any routine laboratory variables, including serum potassium (data not shown) and lipid profiles (Table 4), from baseline to 24 or 52 weeks in any of the treatment groups. No significant changes in mean creatinine clearance were observed over the 52 weeks of the study in any of the treatment groups (Table 4).
4. Discussion In the present study, dual RAS blockade using the ARB telmisartan and an ACE inhibitor lisinopril was associated with a greater reduction in blood pressure and improvement in AER than that observed with either lisinopril or telmisartan monotherapy in type 2
Lisinopril + telmisartan
diabetic hypertensive patients with microalbuminuria. Combined treatment for 28 weeks revealed additive effects on the normalisation of microalbuminuria. The combined therapy was well tolerated and safe, with no evidence of hyperkalaemia or hypotension. The safety of a combination of an ARB and an ACE inhibitor has been observed previously [30–33]. Microalbuminuria is an early marker of diabetic nephropathy, particularly in individuals with type 2 diabetes, and its prevention is considered a primary objective in type 2 diabetes management[34]. Many studies have shown that ACE inhibitors can reduce microalbuminuria and slow the progression of renal disease in hypertensive type 2 diabetic patients [35]. In general, the beneficial effects of ACE inhibitors are thought to be due to a reduced generation of angiotensin II, which has been implicated in the early stages of chronic kidney disease in both plasma and tissues [36]. ACE inhibitors also inhibit kininase activity, leading to an accumulation of bradykinin and other vasodilatory prostaglandins. Although these substances may enhance vasodilation induced by ACE inhibitors, they may cause coughing and occasionally angioedema [37]. Development of ARBs has provided a useful, alternative class of antihypertensive agents to manip-
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ulate angiotensin II activity [38]. As they are highly selective to the AT1 receptor, they provide more specific blockade of angiotensin II than ACE inhibitors. Our results emphasise the central role of RAS blockade in mediating the renoprotective effects of an ACE inhibitor or an ARB. The Reduction of End points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated the greater beneficial effect of an ARB compared with conventional antihypertensive agents on the composite endpoint of doubling of baseline serum creatinine, ESRD, or death in patients with type 2 diabetes and proteinuria [39]. This superior renoprotective effect with the ARB was obtained despite virtually identical blood pressure reductions compared with conventional antihypertensive therapy. Our study provides evidence of an important role for combination therapy in hypertensive type 2 diabetic patients with microalbuminuria. The reduction in microalbuminuria could be explained by the renoprotective effect, due to a reduction in blood pressure [40] and/or by blockade of uncontrolled angiotensin peptide (such as angiotensin III and IV) production [40]. In a study in rats, a combination of an ACE inhibitor and ARB reduced levels of angiotensin II in plasma and kidney to a greater extent than either monotherapy given at higher doses [41]. This reduction in angiotensin II levels with dual blockade provides a mechanism for understanding the beneficial synergistic effects on AER and blood pressure, and may have important implications in long-term organ protection in patients with hypertension and chronic kidney disease [42]. The Candesartan and Lisinopril Microalbuminuria (CALM) study in type 2 diabetic patients with hypertension and microalbuminuria demonstrated an enhanced blood pressure reduction using a combination of 16 mg of candesartan cilexetil and 20 mg of lisinopril administered for 12 weeks compared with monotherapy [31]. The authors of the CALM study acknowledged the need for additional long-term studies, as the possibility of ACE escape following the longer-duration administration of an ACE inhibitor was not addressed. It has been shown, for example, that angiotensin II concentrations are restored to pre-treatment levels after 6 months of ACE inhibitor administration [43].
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In our study, the renoprotective effect of dual RAS blockade was demonstrated after 52 weeks of treatment.
5. Conclusions The results of our study suggest that telmisartan can reduce AER as effectively as lisinopril in type 2 diabetic patients with hypertension and microalbuminuria. Furthermore, dual RAS blockade using a combination of telmisartan and lisinopril provides additional renoprotection by further reducing both blood pressure and AER, and is well tolerated. These findings point to a new therapeutic approach to the prevention of overt diabetic nephropathy in patients with type 2 diabetes, hypertension and microalbuminuria.
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Beneficial effect of lisinopril plus telmisartan in patients with type 2 diabetes, microalbuminuria and hypertension Ahmet M. Sengul *, Yu¨ksel Altuntas, Akın Ku¨rklu¨, Levent Aydın Department of 2nd Internal Medicine, Division of Endocrinology and Diabetes, Sisli Etfal Education and Research Hospital, Istanbul, Turkey Received 14 December 2004; received in revised form 12 April 2005; accepted 23 June 2005 Available online 19 August 2005
Abstract Angiotensin-converting enzyme (ACE) inhibitors have favourable effects on hypertension and diabetic nephropathy, but persistent use may result in incomplete blockade of the renin–angiotensin system. Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker (ARB) telmisartan on blood pressure and albumin excretion rate (AER) were evaluated. Patients with type 2 diabetes mellitus, hypertension (systolic blood pressure [SBP] 140 mmHg or diastolic blood pressure [DBP] 90 mmHg) and microalbuminuria (AER 30–300 mg/24 h) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks. Patients were then randomised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks. Significant (P < 0.001) declines in SBP (11.1 mmHg versus 10.0 mmHg), DBP (5.6 mmHg versus 5.3 mmHg) and AER (98 mg/24 h versus 80 mg/24 h) were achieved with lisinopril (n = 95) or telmisartan (n = 97), respectively, after 24 weeks. Subsequent treatment with lisinopril plus telmisartan for 28 weeks resulted in further significant reductions (P < 0.001) in SBP, DBP and AER compared with either monotherapy. All treatments were well tolerated. Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy. We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes, hypertension and microalbuminuria. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Diabetes mellitus; Hypertension; Microalbuminuria; Lisinopril; Telmisartan; Combination therapy
1. Introduction Diabetes is the most common cause of end-stage renal disease (ESRD) in the western world [1]. In the * Corresponding author. Tel.: +90 212 660 20 07; fax: +90 212 660 20 07. E-mail address: [email protected] (A.M. Sengul).
USA, diabetic nephropathy accounts for nearly 40% of new cases of ESRD, and 20–30% of patients with type 1 or type 2 diabetes develop overt nephropathy [2], characterised by persistent microalbuminuria, elevated blood pressure and a decline in the creatinine clearance, ultimately leading to ESRD [3]. Microalbuminuria, in addition to being the earliest manifestation of nephropathy, is a strong risk factor for
0168-8227/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2005.06.010
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all-cause and cardiovascular mortality in patients with either type 1 or 2 diabetes [4–6]. The benefits of angiotensin-converting enzyme (ACE) inhibitors in diabetic nephropathy are well documented [7–10], notably reducing the incidence of diabetic nephropathy in both hypertensive and normotensive type 1 or 2 diabetic patients with microalbuminuria [11]. In addition, they reduce the rate of mortality [12] and the need for dialysis or a kidney transplant in patients with type 1 diabetes and overt nephropathy [13]. ACE inhibitors are thought to act within the kidneys by reducing efferent arteriolar pressure, thereby decreasing intraglomerular pressure and reducing albumin excretion [14]. Furthermore, they act on the endothelium and decrease vascular smooth muscle growth, decrease release of endothelin, and increase fibrinolysis and release of vasodilatory substances, such as nitric oxide and prostacyclin, mediated by bradykinin [15]. Renoprotective effects of ACE inhibitors are a result of the suppressed generation of angiotensin II in both plasma and tissues. However, in many people, ACE inhibitor monotherapy fails to achieve blood pressure targets [16] and, in patients with chronic kidney disease, many progress to ESRD [17]. The unsatisfactory antihypertensive response may be explained by incomplete blockade of the renin–angiotensin system (RAS), the ‘ACE escape’ phenomenon [18] leading to the generation of angiotensin II by alternative ACEindependent pathways, such as chymase [19]. Angiotensin II receptor blockers (ARBs) also target the RAS, but lower blood pressure by preventing the binding of angiotensin II to type 1 (AT1) receptors. The ARBs appear to be as effective as ACE inhibitors in renoprotection [20,21]. The possibility of combining an ACE inhibitor with an ARB, rather than using a supramaximal dose of an ACE inhibitor, has been a matter of debate [22]. To date, benefits have been demonstrated in the short-term, but the results have not been consistent in all studies [23]. Furthermore, the longer-term advantages of administering an ACE inhibitor and an ARB have yet to be demonstrated. In this prospective, randomised study, we evaluated the long-term effect of dual blockade of the RAS using a combination of an ACE inhibitor (lisinopril) and an ARB (telmisartan) with a long terminal elimination half-life [24] and long duration of action [25,26], on blood pressure and the albumin excretion rate (AER)
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in diabetic, hypertensive patients with persistent microalbuminuria.
2. Materials and methods 2.1. Patient selection The study was conducted in 219 patients with type 2 diabetes based on World Health Organization criteria [27]. Patients were between 40- and 65year-old and had previously diagnosed hypertension (systolic blood pressure [SBP] 140 mmHg or diastolic blood pressure [DBP] 90 mmHg), despite receiving ACE inhibitor monotherapy for 6 months, and microalbuminuria (AER rate 30–300 mg/24 h for a minimum of three consecutive occasions). Exclusion criteria were type 1 diabetes, body mass index 40 kg/ m2, secondary diabetes, alcoholism, thyroid disease, SBP >200 mmHg, any non-diabetic cause of secondary hypertension (including bilateral renal artery stenosis), urinary tract infection, persistent haematuria, chronic liver disease, overt carcinoma, any cardiovascular event in the previous 6 months, serum creatinine 150 mmol/l, serum potassium 5.5 mmol/l or pregnancy. All patients were required to give informed consent to participate after the nature of the study had been explained. 2.2. Study design The randomised, parallel-group, open-label, crossover, prospective study was performed in accordance with the Helsinki Declaration, and with local Ethical Committee approval. There was an initial 2-week wash-out period before eligible patients were assigned to treatment of 20 mg of lisinopril (n = 110) or 80 mg of telmisartan (n = 109), administered after breakfast and before 09:00 a.m. once a day for 24 weeks (Fig. 1). After 24 weeks, half of the patients receiving lisinopril were randomised to receive 80 mg of telmisartan once a day in addition. Similarly, half the patients initially treated with telmisartan received a combination of 20 mg of lisinopril plus 80 mg of telmisartan. The remaining patients continued to be treated with monotherapy. Treatment was continued for a further 28 weeks. The treatment was individualised in both groups according to blood pressure throughout the
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SBP and DBP were measured in the morning about 24 h after the previous drug administration (trough value) using an automatic device (Omron HEM-705 CP, Omron Electronics, Tokyo, Japan) with the patient having been seated for 10 min. The mean of the three measurements taken at 5-min intervals was recorded. Blood pressure was also measured once after the patient had been standing for 2 min. Microalbuminuria was determined using turbidimetry (Cobas Mira Plus, Roche, Montclaire, NJ, USA) as the geometric mean of AER of three consecutive 24-h urine collections. The intra-assay and interassay coefficients of variation were 3.4 and 5.0%, respectively. Creatinine clearance was calculated with the Cockcroft–Gault formula: Fig. 1. Design of study to evaluate the effect of once-daily lisinopril 20 mg and/or telmisartan 80 mg on blood pressure and microalbuminuria in patients with type 2 diabetes.
study period with the addition of hydrochlorothiazide. Patients were instructed to follow a normocaloric diet (30 kcal/kg) with a sodium level of about 150 mmol/day and a constant amount of protein (1.2 g/kg). Lifestyle and diabetes treatment remained unchanged throughout the study. Patients were withdrawn if any of the following occurred: serum potassium >5 mmol/l, SBP 200 mmHg and/or DBP 60 mmHg and/or returned medication exceeded 5% of expected. 2.3. Measurements During the study, the patients attended a clinic on seven occasions: screening, randomisation after the 2-week wash-out, and 6, 12, 24, 36 and 52 weeks after the initial randomisation. Drug compliance was confirmed by a tablet count of returned medication. Blood samples were collected after an overnight fast of 12 h. Patients were also examined for retinopathy at each visit by the same ophthalmologist. At the screening visit, AER and seated blood pressure were measured, and serum potassium and creatinine were determined. At each subsequent visit, blood pressure, AER, plasma glucose, glycosylated haemoglobin (HbA1c), serum potassium, lipid profiles and creatinine clearance were determined.
140 age ðyearsÞ weight ðkgÞ K serum creatinine ðmmol=lÞ where K was 1.25 for men and 1.4 for women. HbA1c was measured by high-performance liquid chromatography using a commercial kit (Bio-Rad); reference levels were 4–6% and the interassay coefficient of variation was 3%. Serum triglycerides and cholesterol were determined by enzymatic colorimetric methods using kits (Boehringer Mannheim GmbH, Diagnostica, Mannheim, Germany). High-density lipoprotein cholesterol was measured by a precipitation-based method with phosphotungstic acid [28]. Low-density lipoprotein cholesterol was calculated using Friedewald’s formula [29]. Plasma glucose was determined by the glucose oxidase method (GOD-Perid, Boehringer Mannheim, Mannheim, Germany). Serum potassium, sodium, creatinine and cholesterol concentrations were assayed using a BM-Hitachi system (Boehringer Mannheim GmbH, Roche Laboratory Systems, Mannheim, Germany). Tolerability was assessed at each visit by spontaneously reported adverse events recorded in response to an open question or observed by the investigator. 2.4. Statistical analysis Data were analysed using SPSS version 11.0 (SPSS, Chicago, IL, USA). Normally distributed variables were expressed as mean S.D. and otherwise as median (range). Changes in variables between visits were expressed as the mean values together with
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95% confidence intervals (CI). Differences in AER within the groups were compared using Student’s t-test, and differences between the groups regarding the change in UAE were compared using ANOVA. For all treatment groups, the changes in arterial blood pressure and creatinine clearance from baseline to 24 and 52 weeks were analysed using a linear model for analysis of covariance (ANCOVA), with treatment, interaction between treatments and baseline value as covariates. For AER, ANCOVA was used with changes in SBP, DBP and body weight used as covariates. Linear regression analysis was employed to establish any correlation between changes in blood pressure and relative change in GFR. Spearman‘s rank correlation coefficient was employed to determine the correlation between the change in blood pressure and the change in microalbuminuria. A P-value of < 0.05 was considered statistically significant (two-sided test).
3. Results 3.1. Patient baseline characteristics Baseline characteristics of the 219 enrolled patients are summarised in Table 1. There were no statistically
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significant differences between the two groups with respect to age, body mass index, plasma lipid profiles, duration of diabetes mellitus, HbA1c, serum creatinine, blood pressure and smoking habits. Seventy-six patients assigned to telmisartan treatment and 77 patients assigned to lisinopril were taking oral antidiabetic drugs; the remainder (33 patients in each group) were being treated with insulin. The antidiabetic treatment regimens remained relatively constant throughout the study period. In addition, 12.5 mg of hydrochlorothiazide once a day was used to treat 19 patients in the telmisartan group and 21 in the lisinopril group. In total, 27 patients were excluded from the study: 15 on lisinopril due to discontinuation of the study protocol or side-effects of the drug such as nausea, stomach upset, respiratory infection, cough, headache, dizziness or feeling weak and 12 on telmisartan due to nausea, headache, dizziness, stomach upset, cough, gastrointestinal problems and withdrawal of consent. Retinopathy was present in 72 patients randomized to telmisartan and 73 who were receiving lisinopril, but it was not proliferative. There were no differences in the prevalence of neuropathy and other macroangiopathic complications between the groups at baseline and during the 52-week study.
Table 1 Baseline characteristics of patients with hypertension, microalbuminuria and type 2 diabetes followed from baseline to 24 weeks of monotherapy Telmisartan (n = 109)
Lisinopril (n = 110)
Sex (female/male) Age (years) Body mass index (kg/m2) Duration of diabetes (years) Smokers, n (%) SBP (mmHg) DBP (mmHg)
69/40 56.5 8.2 30.6 4.2 11.7 7.1 39 (35.8) 150.4 14.2 89.9 5.4
68/42 56.7 8.3 30.1 3.9 11.8 7.0 41 (37.3) 151.2 14.4 87.9 5.2
AER (mg/24 h) Median Range
256 140–300
264 150–300
Serum creatinine (mmol/l) Creatinine clearance (ml/min) HbA1c (%) Serum potassium (mmol/l) Total cholesterol (mg/dl) LDL cholesterol (mmol/l) Triglycerides (mmol/l)
85.6 18.4 97.2 20.1 7.9 1.4 4.2 0.4 5.2 2.3 3.36 1.4 2.2 1.0
85.4 17.4 96.4 20.0 7.8 1.2 4.3 0.4 5.7 2.4 3.6 1.6 2.1 0.9
SBP, systolic blood pressure; DBP, diastolic blood pressure; AER, urinary albumin excretion rate; HbA1c, glycosylated haemoglobin; LDL, lowdensity lipoprotein. Values are mean S.D. unless stated otherwise.
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Table 2 Adjusted reductions (95% confidence intervals [CI]) in blood pressure and urinary albumin excretion rate (AER) from baseline to 24 weeks of monotherapy Telmisartan
Lisinopril
Adjusted mean difference between treatmentsa
95% CI
P-value
SBP (mmHg) Mean Range P vs. baseline
10.0 7.1–14.5 <0.001
11.1 9.3–16.7 <0.001
1.1
1.1, 3.3
>0.2
DBP (mmHg) Mean Range P vs. baseline
5.3 3.1–8.2 <0.001
5.6 3.6–9.1 <0.001
0.3
1.0, 2.1
>0.2
AER (mg/24 h) Mean Range P vs. baseline
80 74–105 <0.001
98 80–124 <0.001
18
0, 37
0.12b
SBP, systolic blood pressure; DBP, diastolic blood pressure. a Adjusted for treatment, baseline value, weight and change in DBP. b Relative reduction.
3.2. Efficacy SBP and DBP fell significantly from baseline (P < 0.001 for both monotherapies; Table 2); there was no statistically significant difference between treatments (P > 0.05). Significant declines from baseline in AER were observed at 24 weeks (Table 2), decreasing by 31.3% from a median of 256 mg/24 h
(range 140–300 mg/24 h) to 176 mg/24 h (range 80– 220 mg/24 h) (P < 0.001) with telmisartan and by 37.1% from a median of 264 mg/24 h (range 150– 300 mg/24 h) to 166 mg/24 h (range 90–220 mg/24 h) with lisinopril (P < 0.001). The difference between treatments was not significant (P > 0.05). Table 3 shows the characteristics of the four groups at week 24 followed to week 52. Patients who were
Table 3 Characteristics of patients followed from 24 to 52 weeks Telmisartan (n = 48)
Lisinopril (n = 48)
Telmisartan + lisinopril (n = 49)
Lisinopril + telmisartan (n = 47)
Sex (female/male) Age (years) BMI (kg/m2) Duration of diabetes (years) SBP (mmHg) DBP (mmHg)
30/18 56.4 8.0 30.4 4.0 11.6 7.0 140.4 14.0 84.6 7.0
31/17 57.2 8.0 30.2 3.9 11.0 7.8 140.1 13.2 82.3 6.6
29/20 56.9 8.2 30.9 4.1 11.1 6.8 140.2 13.4 83.4 6.7
29/18 57.0 8.3 31.0 4.2 11.3 6.7 139.5 13.0 82.0 6.5
AER (mg/24 h) Median Range
176 80–220
166 90–220
174 55–212
175 45–205
Serum creatinine (mmol/l) Serum potassium (mmol/l) Creatinine clearance (ml/min) HbA1c (%) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mmol/l)
86.2 18.2 4.2 0.4 94.2 19.4 7.9 1.4 5.5 2.1 3.5 1.1 2.4 1.0
84.4 17.2 4.5 0.4 96.2 20.1 7.6 1.2 5.5 2.2 3.4 1.2 2.4 1.1
85.2 17.9 4.3 0.4 93.2 18.4 7.3 1.3 5.4 2.1 3.5 1.2 2.3 1.0
82.2 19.2 4.4 0.4 94.1 19.2 7.5 1.4 5.6 2.0 3.6 1.2 2.5 1.1
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AER, urinary albumin excretion; HbA1c, glycosylated haemoglobin. All figures are mean S.D., unless stated otherwise.
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founders, including gender, HbA1c, lipids, diabetes treatment, baseline values, body mass index, weight, age, duration of diabetes, smoking, serum creatinine, creatinine clearance and serum potassium. In the groups of patients who received the combination therapy, there was a measurable further reduction in AER (P < 0.001; Table 6). From baseline to week 52, percentage reductions in AER with telmisartan, lisinopril, telmisartan plus lisinopril and lisinopril plus telmisartan were 36.0, 40.5, 52.7 and 53.6%, respectively. AER was reduced to within the normal range (<30 mg/24 h) in eight patients in the lisinopril plus telmisartan group and in seven patients in the telmisartan plus lisinopril group at 52 weeks. On the other hand, AER was not reduced within the normal range in either monotherapy group at 24 or 52 weeks.
withdrawn from the study up until the 24-week visit were not included in the 52-week evaluation. After 52 weeks’ active treatment, data were available for 48 patients treated with telmisartan, 48 treated with lisinopril, 49 treated with telmisartan plus lisinopril and 47 treated with lisinopril plus telmisartan. Some patients in each treatment group also received 12–5 mg of hydrochlorothiazide once a day to achieve superior reductions in blood pressure: telmisartan (n = 9), lisinopril (n = 10), telmisartan plus lisinopril (n = 7), lisinopril plus telmisartan (n = 8). All treatments reduced AER (Table 4) and blood pressure (Table 5) at 52 weeks compared with baseline, with the combination being more effective than either monotherapy. The declines in both AER and blood pressure were independent of any con-
Table 4 The baseline and follow-up median (range) urinary albumin excretion rates (AER), serum creatinine, creatinine clearance and serum lipids
AER (mg/24 h) Baseline 12 weeks 24 weeks 36 weeks 52 weeks
Telmisartan
Lisinopril
Telmisartan + lisinopril
Lisinopril + telmisartan
P-value
256 216 176 170 164
264 224 166 160 157
258 – 174 139 122
259 – 175 140 120
0.431 0.321 0.436 <0.001 <0.001
*
(140–300) (80–245) (80–220) (57–214) (36–190)
(150–300) (100–270) (90–220) (46–200) (34–182)
(132–294) (75–212) (50–174) (23–172)
Serum creatinine (mmol/l) Baseline 85 (80–90) 12 weeks 84 (80–90) 24 weeks 86 (80–91) 36 weeks 85 (81–90) 52 weeks 82 (79–91)
86 85 84 86 83
Creatinine clearance (ml/min) Baseline 97.1 (90–100) 12 weeks 96.4 (89–99) 24 weeks 94.2 (80–98) 36 weeks 93.3 (88–96) 52 weeks 94.1 (90–98)
96.2 94.2 95.5 94.3 95.3
LDL cholesterol (mg/dl) Baseline 3.4 (1.4–4.5) 12 weeks 3.3 (1.3–4.3) 24 weeks 3.5 (1.6–4.6) 36 weeks 3.4 (1.2–4.5) 52 weeks 3.6 (1.4–4.8)
3.3 3.4 3.4 3.6 3.5
(1.3–4.4) (1.2–4.4) (1.5–4.7) (1.6–4.8) (1.5–4.6)
3.5 – 3.5 3.6 3.5
(1.4–4.5)
Triglycerides (mmol/L) Baseline 2.2 (1.0–3.2) 12 weeks 2.5 (1.1–3.5) 24 weeks 2.4 (1.3–3.6) 36 weeks 2.3 (1.2–3.5) 52 weeks 2.4 (1.3–3.6)
2.4 2.2 2.4 2.3 2.4
(1.1–3.2) (1.1–3.2) (1.2–3.6) (1.3–3.4) (1.2–3.5)
2.3 – 2.3 2.4 2.5
(1.2–3.4)
*
(80–90) (81–90) (82–91) (81–91) (80–92) (90–100) (88–98) (81–99) (88–96) (89–97)
p < 0.001 for both 36 and 52 weeks of treatment.
84 – 85 84 84
(79–90) (79–91) (80–90) (80–90)
95.3 – 93.4 95.3 94.4
(89–99) (88–98) (89–97) (88–98)
(1.5–4.8) (1.3–4.6) (1.4–4.7)
(1.4–3.5) (1.2–3.5) (1.4–3.6)
83 – 87 83 83
(141–292) (78–205) (40–170) (22–151)
(80–90) (81–90) (80–92) (79–91)
94.2 – 95.4 96.5 95.4
(89–100) (88–98) (90–98) (89–97)
3.5 – 3.6 3.5 3.4
(1.3–4.4)
2.2 – 2.5 2.4 2.4
(1.1–3.3)
(1.5–4.8) (1.4–4.5) (1.5–4.8)
(1.2–3.6) (1.3–3.7) (1.3–3.5)
0.412 0.422 0.436 0.322 0.345 0.420 0.329 0.336 0.401 0.388 0.424 0.329 0.430 0.396 0.404 0.429 0.367 0.466 0.349 0.398
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Table 5 Adjusted mean reduction and 95% confidence intervals (CI) in seated systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 52 weeks Telmisartan
Lisinopril
Telmisartan + lisinopril
Lisinopril + telmisartan
Mean
95% CI
Mean
95% CI
Mean
95% CI
Mean
95% CI
P-value (between treatment groups)
SBP (mmHg)
15.1 P < 0.001
9.1, 19.3
16.4 P < 0.001
11.1, 19.3
25.5 P < 0.001
16.0, 30.0
25.2 P < 0.001
16.7, 29.8
0.003
DBP (mmHg)
10.2 P < 0.001
7.1, 12.1
10.4 P < 0.001
7.8, 13.1
15.4 P < 0.001
12.6, 17.8
15.2 P < 0.001
12.4, 17.4
0.003
Table 6 Adjusted mean (95% confidence intervals [CI]) reduction in urinary albumin excretion rate (AER) from baseline to 52 weeks Telmisartan
AER (mg/24 h)
Lisinopril
Telmisartan + lisinopril
Mean
95% CI
Mean
95% CI
Mean
95% CI
Mean
95% CI
P-value (between treatment groups)
92 P < 0.001
42, 124
107 P < 0.001
34, 148
136 P < 0.001
24, 172
139 P < 0.001
23, 181
0.04
None of the patients receiving either monotherapy or combination therapy developed macroalbuminuria (AER >300 mg/24 h). 3.3. Tolerability and safety All treatment regimens were well tolerated. The most frequent adverse events were coughing, occurring exclusively in patients receiving lisinopril, and headache, which were experienced by less than 10% of the patients. There were no significant changes in mean values for HbA1c or any routine laboratory variables, including serum potassium (data not shown) and lipid profiles (Table 4), from baseline to 24 or 52 weeks in any of the treatment groups. No significant changes in mean creatinine clearance were observed over the 52 weeks of the study in any of the treatment groups (Table 4).
4. Discussion In the present study, dual RAS blockade using the ARB telmisartan and an ACE inhibitor lisinopril was associated with a greater reduction in blood pressure and improvement in AER than that observed with either lisinopril or telmisartan monotherapy in type 2
Lisinopril + telmisartan
diabetic hypertensive patients with microalbuminuria. Combined treatment for 28 weeks revealed additive effects on the normalisation of microalbuminuria. The combined therapy was well tolerated and safe, with no evidence of hyperkalaemia or hypotension. The safety of a combination of an ARB and an ACE inhibitor has been observed previously [30–33]. Microalbuminuria is an early marker of diabetic nephropathy, particularly in individuals with type 2 diabetes, and its prevention is considered a primary objective in type 2 diabetes management[34]. Many studies have shown that ACE inhibitors can reduce microalbuminuria and slow the progression of renal disease in hypertensive type 2 diabetic patients [35]. In general, the beneficial effects of ACE inhibitors are thought to be due to a reduced generation of angiotensin II, which has been implicated in the early stages of chronic kidney disease in both plasma and tissues [36]. ACE inhibitors also inhibit kininase activity, leading to an accumulation of bradykinin and other vasodilatory prostaglandins. Although these substances may enhance vasodilation induced by ACE inhibitors, they may cause coughing and occasionally angioedema [37]. Development of ARBs has provided a useful, alternative class of antihypertensive agents to manip-
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ulate angiotensin II activity [38]. As they are highly selective to the AT1 receptor, they provide more specific blockade of angiotensin II than ACE inhibitors. Our results emphasise the central role of RAS blockade in mediating the renoprotective effects of an ACE inhibitor or an ARB. The Reduction of End points in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated the greater beneficial effect of an ARB compared with conventional antihypertensive agents on the composite endpoint of doubling of baseline serum creatinine, ESRD, or death in patients with type 2 diabetes and proteinuria [39]. This superior renoprotective effect with the ARB was obtained despite virtually identical blood pressure reductions compared with conventional antihypertensive therapy. Our study provides evidence of an important role for combination therapy in hypertensive type 2 diabetic patients with microalbuminuria. The reduction in microalbuminuria could be explained by the renoprotective effect, due to a reduction in blood pressure [40] and/or by blockade of uncontrolled angiotensin peptide (such as angiotensin III and IV) production [40]. In a study in rats, a combination of an ACE inhibitor and ARB reduced levels of angiotensin II in plasma and kidney to a greater extent than either monotherapy given at higher doses [41]. This reduction in angiotensin II levels with dual blockade provides a mechanism for understanding the beneficial synergistic effects on AER and blood pressure, and may have important implications in long-term organ protection in patients with hypertension and chronic kidney disease [42]. The Candesartan and Lisinopril Microalbuminuria (CALM) study in type 2 diabetic patients with hypertension and microalbuminuria demonstrated an enhanced blood pressure reduction using a combination of 16 mg of candesartan cilexetil and 20 mg of lisinopril administered for 12 weeks compared with monotherapy [31]. The authors of the CALM study acknowledged the need for additional long-term studies, as the possibility of ACE escape following the longer-duration administration of an ACE inhibitor was not addressed. It has been shown, for example, that angiotensin II concentrations are restored to pre-treatment levels after 6 months of ACE inhibitor administration [43].
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In our study, the renoprotective effect of dual RAS blockade was demonstrated after 52 weeks of treatment.
5. Conclusions The results of our study suggest that telmisartan can reduce AER as effectively as lisinopril in type 2 diabetic patients with hypertension and microalbuminuria. Furthermore, dual RAS blockade using a combination of telmisartan and lisinopril provides additional renoprotection by further reducing both blood pressure and AER, and is well tolerated. These findings point to a new therapeutic approach to the prevention of overt diabetic nephropathy in patients with type 2 diabetes, hypertension and microalbuminuria.
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