Hypertension, albuminuria and decreased GFR are regarded as independent risk factors that reflect progression of diabetic kidney disease (DKD). We carried out a phase 2 prospective study which aimed to determine the possibility of implementation of intensive antihypertensive therapy into the routine clinical practice and assessment of the impact of such treatment on kidney function in patients with type 2 diabetes mellitus (T2DM)`
Hypertension, albuminuria and decreased GFR are regarded as independent risk factors that reflect progression of diabetic kidney disease (DKD). We carried out a phase 2 prospective study which aimed to determine the possibility of implementation of intensive antihypertensive therapy into the routine clinical practice and assessment of the impact of such treatment on kidney function in patients with type 2 diabetes mellitus (T2DM)
Methods
In the study 637 patients were included with DKD and arterial hypertension with BP level more than 130/80 mm Hg and less than 180/100 mm Hg, having chronic kidney disease (CKD) stages 1-4. As a basis for intensive antihypertensive treatment, fixed combination of perindopril 5 mg and indapamide 1.25 mg were prescribed. If needed, after 4 weeks the dosage was increased to perindopril 10 mg/ indapamide 2.5 mg to achieve targeted BP less that 130/80 mm Hg. If targeted BP had not been achieved, other antihypertensive preparations were added.
Results
After 4 weeks of treatment, average levels of systolic and diastolic BP were 141.3±0.5 and 86.3±0.3, after 8 weeks of therapy 131.6±0.4 and 81.3±0.3 mm Hg, and after 12 weeks of treatment 1 27.2±0.3 and 78.7±0.2 mm Hg respectively. Target BP was achieved in 489 patients (73.3%) during 12 weeks of treatment. GFR was significantly increased after 12 weeks of antihypertensive therapy with fixed dose perindopril/indapamide combination, from 84.3+1.1 to 94.7+1.1 ml/min./1,73m2, ð<0.01.
Conclusions
Antihypertensive therapy with fixed dose combination of perindopril 5-10 mg/indapamide 1.25-2.5 mg introduced into routine clinical practice of T2DM patients treatment is effective for BP reduction, achievement of BP target values and resulted in a statistically significant trend to kidney function improvement.
Dmitri D. Ivanov, Dept. of Nephrology and Renal Replacement Therapy,
Boris N. Mankovsky, Dept. of Diabetology, National Medical Academy of Postgraduate Education named by P.L. Schupik, Kiev, Ukraine
Correspondence and reprint requests to: Dmitri D. Ivanov; e-mail: [email protected]
Kidney impairment is one of the most serious manifestations of diabetic nephropathy [1]. Hypertension, albuminuria and decreased GFR are regarded as independent risk factors that reflect progression of diabetic kidney disease (DKD) [2]. According to KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease, most people with diabetes and CKD have hypertension and treatment of hypertension slows the progression of CKD [3]. According to 2012 ADA recommendations [4], to reduce the risk or slow the progression of nephropathy, patients need to optimize their glucose control (A) and BP control (A) with an ACE-inhibitors (ACEI) or angiotensin II receptor blockers (ARB), usually in combination with a diuretic.
To determine epidemiologic prevalence of clinical-laboratory manifestations of DKD, using KDOQI criteria [3], in patients with T2DM and to assess antihypertensive treatment efficacy in Ukraine with national population above 46 million, open label, prospective randomize cross-sectional trial “The Scythian” was carried out. The study design had 2 stages. The first one (2008-2009) investigated epidemiologic prevalence and severity of renal damage in T2DM patients (Fig.1). The second stage (2010-2011) studied the efficacy of ACEI perindopril + indapamide for treatment of diabetic nephropathy.
The present work presents the results of the 2nd stage of the trial “The Scythian”, which aimed to study the introduction of intensive antihypertensive treatment into routine clinical practice and assessment of the impact of such therapy effect on kidney function in patients with T2DM. The primary endpoint was to achieve target blood pressure (BP) less than 130/80 mm Hg with fixed combination of perindopril/indapamide. Secondary endpoint was to ascertain renal function trends by estimating GFR.
Six hundred and thirty seven patients with T2DM were enrolled in a prospective study. Inclusion criteria were as follows: established diagnosis of T2DM, age of more than 40 years and diagnosed arterial hypertension of stages 1-2 with BP level more than 130/80 mm Hg and less than 180/100 mm Hg. Exclusion criteria were: stage 3 arterial hypertension, BP level of 180/110 mm Hg and more, type 1 diabetes mellitus, age less than 40 years, history of myocardial infarction, cerebrovascular event in the previous 6 months before the study , polycystic kidney disease, malignancy , pregnancy or breast feeding, anemia at hemoglobin level less than 90 g/L.
As a basis for intensive antihypertensive treatment fixed combination of perindopril 5 mg + indapamide 1.25 mg was selected. The reason for selection of this combination were the results of the ADVANCE study, where in large populations of patients (more than 11,000 patients with T2DM), it was demonstrated that this prescription as the background standard antihypertensive therapy resulted in reduction of all-cause mortality by 14%, cardiovascular mortality by 18%, and development of diabetic renal complications by 21% [6].
The study was carried out according to the algorithm shown in fig. 1 with ethical approval from National Academy of Postgraduate Education and patients signed informed consent. With BP level more than 130/80 mm Hg, the patients were prescribed fixed dose combination of perindopril 5 mg + indapamide 1.25 mg once a day in the morning. In the absence of prior antihypertensive therapy, the fixed combination was prescribed as monotherapy. If the patients were receiving calcium channel blockers (CCB) or ?-blockers (?Bs), fixed combination was prescribed as additional therapy. If patients were initially receiving ACEI, ARB, or a combination which included ACEI or ARB, this treatment was discontinued and fixed combination of perindopril 5 mg + indapamide 1.25 mg was prescribed. BP measurement was performed 4 weeks after commencement of perindopril/indapamide combination treatment. If the BP level achieved target level of less than 130/80 mm Hg, the patient continued treatment at the same dose. If BP levels remained high, the dosage was increased twofold up to 10 mg of perindopril and 2.5 mg of indapamide. In 8 weeks, BP measurements were repeated and if necessary, additional antihypertensive preparations were a prescribed to achieve the target BP below 130/80 mm Hg. BP levels were evaluated by office measurements on three consecutive days.
After 12 weeks of the trial initiation, the BP levels were provided to the patients and GFR was calculated. GFR index was calculated on the basis of serum creatinine levels by the Cockcroft & Gault formula [7]. The serum creatinine was measured using the modified Jaffe method in local certificated laboratories.
The majority of patients were on antihypertensive therapy at baseline: 452 patients (67.8%) were treated with ACEI, 58 patients (8.7%) were taking ARB, 171 (25.6%) patients CCB, 218 (32.7%) patients ?B, 235 (35.2%) patients diuretics, 26 patients (3.9%) ?-blockers. However, only 340 patients (51%) received antihypertensive preparations regularly. The majority of patients (61.6%) received combined antihypertensive therapy. Low sodium diet was recommended to all patients .
Obesity, defined as body mass index more than 30 kg/m2 in both genders, was reported in 386 (53%) of patients, 289 (43.5%) patients had excess body mass with body mass index more than 25 kg/m2.
The majority of patients (563 patients 86.9%) received oral hypoglycemic agents, while insulin therapy was prescribed for 60 patients (9.2%) and 25 persons (3.9%) received both oral hypoglycemic agents and insulin.
Statistical analysis of data was carried out using online Creative Research Systems calculator of statistical significance [8]. The Microsoft PowerPoint 2010 and Microsoft Excel were used to tabulate and process the data.
There were 289 (45.4%) male and 348 (54.6%) female patients included in this trial. The mean age of the patients was 58±0.6 years (Ì ± SD), average diabetes duration of 7±0.3 years. Baseline creatinine level was 101±1.2 ?mol/L, GFR 84±1.1 mL/min./1.73ì2. Mean baseline systolic BP was 162±0.5 mm Hg, mean baseline diastolic BP 95±0.3 mm Hg. 48% of patients had macroalbuminuria and 52% had microalbuminuria detected by dipstick tests.
Significant reduction of systolic and diastolic BP was achieved (Fig. 2). In 4 weeks of treatment, average systolic and diastolic blood pressure were 141.3±0.5 and 86.3±0.3 mm Hg; in 8 weeks of therapy 131.6±0.4 and 81.3±0.3 mm Hg; and in 12 weeks of treatment- 127.2±0.3 and 78.7±0.2 mm Hg, respectively. In absolute numbers, systolic BP reduction for the period of treatment was 34.7 mm Hg, diastolic BP reduction 16.5 mm Hg, p<0.001, compared to baseline levels before start of the therapy with fixed dose combination of perindopril/indapamide. It is important to emphasize that at the end of follow-up period among patients (n=353) receiving perindopril 5 mg/indapamide 1.25 mg as monotherapy in a dose of 1 tablet a day, average arterial pressure values were 128.5±0.6 and 79.9±0.5 mm Hg, while in those who received perindopril 10 mg/indapamide 2.5 a day (n=284) the values of systolic and diastolic BP were 123.4±0.5 and 76.7±0.4 mm Hg, respectively.
In absolute numbers in the group of patients, receiving daily perindopril 5 mg/indapamide 1.25 mg (n=353), reductions of systolic and diastolic BP for the time of treatment were 33.7 mm Hg and 17 mm Hg, respectively, ð<0,001, compared to the baseline. In the group of patients who took daily perindopril 10 mg/indapamide 2.5 mg (n=284), reductions of systolic and diastolic BP for the time of treatment were 38.4 mm Hg and 15.8 mm Hg, respectively, ð<0,001, compared to the baseline.
Target BP below 130/80 mm Hg (according to guidelines [4, 9]) was achieved in 171 patients (25.6%) in 4 weeks, in 373 patients (55.9%) in 8 weeks after treatment initiation, and in 489 (73.3%) patients in 12 weeks of treatment. Thus, 148 patients (26.7%) needed to add/increase CCB or ?B to reach targeted BP after 12 weeks of perindopril/indapamide. Among the patients with baseline BP level below 160/100 mm Hg, at the end of 12weeks follow-up BPs were at target in 87.5% of patients (n=557), and among persons with baseline BP level above 160/100 mm Hg, target BP levels were achieved in 72.5% (n=462). Target BP at the end of 12weeks was achieved in 78.1% of patients (n=497) that initially received ACE inhibitors, in 81.8% of patients (n=521) that previously received angiotensin II receptor blockers, in 74.1% of patients (n=472) previously treated with CCB and in 95.7% of persons (n=610) that received ?B. At the beginning of the study 57,3% of patients (380) used perindopril/indapamide in combination with other antihypertensive drugs while at the end of trial 47,5% (313) did so.
Adequate antihypertensive therapy led to improvements in GFR and albuminuria. Among microalbuminuric patients, 21% were transformed to normoalbuminuria, while 19% of those with macroalbuminuria changed to microalbuminuria. No data were obtained in absolute numbers. Hence, statistically significant GFR increase under the influence of 12week s of antihypertensive therapy with fixed combination of perindopril/indapamide from 84.3+1.1 to 94.7+1.1 mL/min./1,73m2, ð<0.01 (Fig.3) was documented. Proportion of patients with GFR more than 30 and less than 60 mL/min./1,73m2 significantly decreased from 17.6 (n=112) to 8.1% (n=51) (ð<0.001). Statistically significant GFR increase under the influence of antihypertensive therapy was seen independently of the initial BP level. However, correlation between BP reduction and initial GFR value was not established determined (r=0.28).
The first stage of The Scythian trial demonstrated that microalbuminuria is a late sign that follows BP increase and alteration of GFR and characterizes progression of diabetic kidney disease [5]. Urinary microalbumin excretion is one risk factor for progression to overt macroalbuminuria and GFR decline, and other factors were implicated as important for prevention of ESRD [10]. Achievement of target BP values is the most important factor in retarding progression of DKD [11, 4].
Antihypertensive therapy with fixed dose combination of perindopril/indapamide led to achievement of target BP in patients with T2DM included in this study. In our opinion, renal damage may have been influenced by a combination of hypertension and diabetic nephropathy. Hence, any evidence-based prescription seems to be rational in routine practice, demonstrating a significant positive trend in GFR with achievement of BP targets.
In a recent review [12] which included 85 trials and 21708 patients, it was shown that development of ESRD and progression of microalbuminuria to macroalbuminuria were reduced significantly with ACEI versus placebo and ARB versus placebo but not with combined therapy with ACEI+ARB versus monotherapy. A significant reduction in the risk of nonfatal cardiovascular events was observed with ACEI versus placebo, but not with ARB versus placebo, ACEI versus ARB or with combined therapy with ACEI+ARB versus monotherapy [12]. Results of ADVANCE study [6], and a recent review of renal, cardiovascular and mortality endpoints in antihypertensive trials in diabetic patients [13], indicate that therapy selection in favor of ACE inhibitors seems to be rational.
It is important to stress that effectiveness of fixed dose combination of perindopril/indapamide in achieving target BP values did not depend on previous antihypertensive therapy, ranging from 74% of patients receiving initially ÑÑÂ to 96% of patients receiving ?B. In a recent meta-analysis of randomized clinical trials, alternate doses of angiotensin receptor blockers or angiotensin converting enzyme inhibitors in patients with T2DM and microalbuminuria were compared. MEDLINE, EMBASE and the Cochrane Register of Controlled Trials were searched from January 2006 to August 2010. The authors support current recommendations to titrate renin-angiotensin inhibitors to maximum doses whilst recognizing the risk of adverse effects with higher doses [14].
Adequate antihypertensive therapy led to statistically significant GFR increase and a reduction in the number of patients categorized as CKD stage 3 under the influence of 12-week antihypertensive therapy with fixed dose combinations of perindopril/indapamide. Positive GFR modifications were accompanied by a reduction in the number of patients with significant GFR decreasing. On the other hand, significant reduction of arterial pressure values was reported independently on the initial GFR value.
This study demonstrates the possibility of effectively achieving target BP in T2DM patients with perindopril/indapamide fixed dose combinations and an improvement in kidney function. The weakness of this study is the absence of data of strict control of albuminuria levels that does not allow analysis of the correlation between microalbuminuria/creatinine ratios and GFR. With new data, it may be reasonable to use the GFR-EPI calculator for future trials.
The data obtained in The Scynthian trial demonstrate that a reduction to target blood pressure in T2DM patients can be achieved in a short period of time, based on prescription of fixed perindopril (5-10 mg) /indapamide (1,25- 2.5 mg) combination in 73% of the study cohort while adding CCB or ?B is necessary for the rest. With achievement of BP targets, the GFR is improved as well as level of microalbuminuria. In our opinion, antihypertensive therapy with fixed dose perindopril/indapamide combination could be introduced into routine clinical practice in patients with T2DM and hypertension stage 1 or 2 as an effective tool for BP reduction, achievement of BP targeted values and improvement of kidney function.
Conflict of interest statement. The clinical trial was conducted with financial support of Servier company. The authors received lecture fees from Servier.
Acknowledgements. Authors, being project coordinators, express their deep gratitude to the clinicians that participated in the trial.
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- Yokoyama H, Kanno S, Takahashi S et al. Risks for glomerular filtration rate decline in association with progression of albuminuria in type 2 diabetes. Nephrol Dial Transplant (2011) 26:2924-2930.
- Plantinga LC, Miller ER III, Stevens LA, et al. for the Centers for Disease Control Prevention. Chronic Kidney Disease Surveillance Team. BP Control Among Persons Without and With Chronic Kidney Disease. US Trends and Risk Factors 19992006. Hypertension. 2009. – Published online before print May 26, 2009, doi: 10.1161/HYPERTENSIONAHA.109.129841.
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Figure 1. Algorithm of antihypertensive treatment during 2nd stage of The Scythian trial
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