Â Â Objective: This retrospective study compared the efficacy and safety of losartan monotherapy versus losartan and perindopril combination therapy in diabetic patients with hypertension and albuminuria. Factors affecting the change in albuminuria were identified.Methods: Through quota sampling, the study recruited patients from a tertiary care hospital. Outcome parameters included urinary albumin creatinine ratio (UACR), blood pressure (BP), serum creatinine, and estimated glomerular filtration rate (eGFR). Both pre- and post-treatment measurements were traced from patient's medical records.Results: No significant differences (p=0.615) were detected in the pre- and post-treatment change in UACR between the monotherapy group (âˆ’38.3 mg/g, interquartile range [IQR]:âˆ’618.8-0) and combination therapy group (âˆ’88.4 mg/g, IQR: âˆ’729.3-+375.7). There was a considerably higher percentage of patients attaining the target BP of &lt;125/75 mmHg in the combination group (66.7%; p&lt;0.001). In terms of safety, combined losartan and perindopril caused more hypotension (p=0.003), higher rise in serum creatinine (p=0.481), and greater drop in eGFR (p=0.861). Body mass index was shown to have significant negative correlation with UACR reduction (r=âˆ’0.449; p=0.036).Conclusion: The main finding of this study was that losartan alone was as equally efficacious as combined losartan and perindopril in lowering UACR and BP among diabetic patients.Â

Chin, Shin-chee

Md Redzuan, Adyani

English

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Vol 10, Issue 10, 2017Online - 2455-3891 Print - 0974-2441EFFECT OF COMBINING LOSARTAN AND PERINDOPRIL IN DIABETIC PATIENTS WITH PROTEINURIASHIN-CHEE CHIN, ADYANI MD REDZUAN*Quality Use of Medicine Research Group, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia. Email: adyani@ukm.edu.myReceived: 27 May 2017, Revised and Accepted: 04 July 2017ABSTRACTObjective: This retrospective study compared the efficacy and safety of losartan monotherapy versus losartan and perindopril combination therapy in diabetic patients with hypertension and albuminuria. Factors affecting the change in albuminuria were identified.Methods: Through quota sampling, the study recruited patients from a tertiary care hospital. Outcome parameters included urinary albumin creatinine ratio (UACR), blood pressure (BP), serum creatinine, and estimated glomerular filtration rate (eGFR). Both pre- and post-treatment measurements were traced from patient’s medical records.Results: No significant differences (p=0.615) were detected in the pre- and post-treatment change in UACR between the monotherapy group (−38.3 mg/g, interquartile range [IQR]:−618.8-0) and combination therapy group (−88.4 mg/g, IQR: −729.3-+375.7). There was a considerably higher percentage of patients attaining the target BP of <125/75 mmHg in the combination group (66.7%; p<0.001). In terms of safety, combined losartan and perindopril caused more hypotension (p=0.003), higher rise in serum creatinine (p=0.481), and greater drop in eGFR (p=0.861). Body mass index was shown to have significant negative correlation with UACR reduction (r=−0.449; p=0.036).Conclusion: The main finding of this study was that losartan alone was as equally efficacious as combined losartan and perindopril in lowering UACR and BP among diabetic patients.Keywords: Albuminuria, Losartan, Perindopril, Hypertension, Urinary albumin creatinine ratio.INTRODUCTIONThe renin–angiotensin system (RAS) is overactivated when concurrent medical illnesses such as hypertension and diabetes mellitus are present. Although the use of angiotensin-converting enzyme inhibitors (ACEIs) is effective, RAS blockade remains incomplete owing to a counter regulatory  response  caused  by  reactive  hyperreninemia  [1].  This, together with the activation of other tissue enzymes such as chymase, leads  to  the  regeneration  of  plasma  angiotensin  II  [2].  Therefore, an additional agent targeting the RAS is required particularly in preventing disease progression and further complications. In diabetes, a combination therapy of ACEI and angiotensin receptor blocker (ARB) are deemed effective in reducing albuminuria and delaying renal failure.A number of studies have investigated on the efficacy and safety of combining ACEI and ARB in the management of diabetic population with micro- or macro-albuminuria, as defined by urinary albumin creatinine ratio (UACR) of 30-300 mg/g or >300 mg/g, respectively [3]. Two meta-analyses  of  small  controlled  trials  revealed  that  dual  RAS  blockade resulted in additional reduction of UACR and systolic blood pressure (SBP) [4,5]. On the contrary, other studies did not show extra advantages but  more  harm  by  adding  a  second  RAS  blocker  [6,7].  With  these conflicting results, the latest kidney disease outcomes quality initiative guideline does not  yet  recommend dual ACEI  and ARB  treatment  [8]. Further ongoing large-scaled trials are still underway [9,10].The prescribing of combined ACEI and ARB therapy remains widespread currently and is a practice without firm evidence support. This study is carried out to evaluate the effect of combining losartan and perindopril on UACR, BP, serum creatinine, and estimated glomerular filtration rate (eGFR) among a subgroup of diabetic patients with hypertension and albuminuria.METHODSThis retrospective study was approved by the Research Ethic Committee  of  Universiti  Kebangsaan  Malaysia  (UKM1.5.3.5/244/NF-006-2013). Patients taking losartan from January 2012 to January 2013 were retrieved from the pharmacy system. A total of 769 patients were identified. Screening was done to select patients who were diabetics. They were categorized into monotherapy group (losartan alone) and combination group (losartan plus perindopril). Patients’ medical case files were traced from the record unit. At least two UACR readings must be available; pre-treatment UACR was  the UACR reading within 3 weeks before treatment initiation whereas post-treatment UACR was the UACR reading after at least 1 month of treatment. Similarly, pre- and post-treatment BP, serum creatinine, eGFR, and serum potassium were recorded.  eGFR  was  calculated  using  the  Cockcroft-Gault formula. The use of concurrent antihypertensives from other pharmacological classes was allowed, and the regimens were stabilized before the initiation of study drugs. Those who were diagnosed with end-stage renal  failure  and  defaulted  first  follow-up  were  excluded.  Based  on these  inclusion  and  exclusion  criteria,  a  total  number  of  22  patients were recruited as suitable participants (10 receiving losartan alone; 12 receiving concurrent losartan and perindopril).The change in UACR, defined as the difference between pre-and post treatment UACR reading, was evaluated regardless of dosage regimen, together with the change  in BP, serum creatinine, eGFR and serum potassium. Parametric statistical tests were employed for normally distributed continuous data while non-parametric tests for nominal or ordinal data and continuous data with skewed distribution. Correlation analysis was also carried out to investigate determinant factors of UACR reduction. Results were presented in percentage, mean with standard deviation, or median with interquartile range (IQR).© 2017 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4. 0/) DOI: http://dx.doi.org/10.22159/ajpcr.2017.v10i10.20253Research Article358Asian J Pharm Clin Res, Vol 10, Issue 10, 2017, 357-359 Chin and Redzuan RESULTSThe baseline characteristics of patients are presented in Table 1. All patients  were  comparable  in  terms  of  age,  gender,  body mass  index (BMI), smoking status, alcoholic status, and history of  ischemic heart disease  (IHD).  The  majority  of  the  patients  were  Type  II  diabetics, with only a quarter (n=3) in the combination group was diagnosed as Type  I  diabetics.  Macroalbuminuria  was  significantly  more  common in the combination group as compared to the monotherapy group (p<0.001). The pre-treatment readings of outcome parameters among  the  study  groups  did  not  show  significant  differences,  except for UACR reading  (monotherapy 627.64±794.8 mg/g vs.  combination 1856.4±2285.1 mg/g; p=0.012).In  terms  of  the  change  in  UACR  between  pre-  and  post-treatment, there  were  no  significant  differences  (p=0.571)  found  between  the monotherapy  group  (−38.3 mg/g,  IQR:  618.8)  and  combination  group (−88.4 mg/g, IQR: 1105). The result is presented in Table 2. Despite the lack of significant differences in BP reduction between the study groups (change  in SBP, p=0.617; change  in diastolic BP, p=0.695),  there was a higher percentage of participants in the combination group achieving target BP of <125/75 mmHg (p<0.001). The result is presented in Table 3. The changes in serum creatinine (p=0.481) and eGFR (p=0.861) were not significantly affected by the type of therapy; whether it was losartan alone or  losartan  plus  perindopril.  However,  the  combination  regimen  had caused a higher rise in serum creatinine (6.08±18 µmol/L vs. −0.8±16.2 µmol/L) along with a  further drop in kidney function (−1.51±15.4 ml/minute/1.73 m2 vs. −0.56±7.7 ml/minute/1.73 m2).DISCUSSIONLosartan therapy or combined losartan and perindopril therapy were similarly effective in lowering proteinuria and BP. This was supported by results  from ONTARGET trial  [6], although CALM study [11] and a few  meta-analyses  [4,5]  suggested  the  opposite.  Although  the  mean reduction of UACR in the combination group was slightly but not significantly higher than the group on single therapy, this favorable outcome might be offset by the increment in mean serum creatinine along with a reduction in mean eGFR as seen in the current study. The same findings were observed in the ONTARGET and TRANSCEND studies [12]. In other words, for optimal control of proteinuria, we may need to spare the risk of causing more damage on the kidney and hence the loss of renoprotective functions of ACEI and ARB.Both dual and single therapy were good in controlling BP although the former was not significantly more effective than the latter. The total antihypertensive responses were minor, but this should not be neglected  in  the current study because as  little as 2-3 mmHg drop  in SBP could contribute to a cardiovascular risk reduction of 4-5% [13]. A greater proportion of patients managed to achieve target BP with the use of combined losartan and perindopril. Nonetheless, more patients in the combination group had developed hypotension (p=0.003). This could be explained by the synergistic action of losartan and perindopril on RAS, resulting in further drops in BP.In  the  current  study,  a  significant  negative  correlation  was  found between  the patient’s BMI  and UACR  reduction  (r=−0.449; p=0.036). Table 1: Baseline characteristics of the study population according to therapy groupCharacteristics Monotherapy (n=10) Combination therapy (n=12) p-valueAge (year; mean±SD) 61±2 53±4 0.09Gender (M/F) 6/4 7/5 0.64BMI (kg/m2) 28.7±5.7 28.2±4.1 0.79Smoker (%) 30 25 0.53Alcoholic (%) 20 25 0.50Duration of hypertension (%)<10 years 30 50 0.006>10 years 70 50Diabetes mellitus (%)Type I 0 25 <0.001Type II 100 75Duration of DM (%)<5 years 30 25 0.595-10 years 20 25>10 years 50 50Diabetic kidney disease (%) 10 42 <0.001Existing renal diseasesa (%) 90 58 <0.001Previous IHD/CAD (%) 20 33 0.054Type of albuminuria (%)Microalbuminuria 50 0 <0.001Macroalbuminuria 50 100UACR (mg/g; mean±SD) 627.64±794.8 1856.4±2285.1 0.012SBP (mmHg; mean±SD) 146±11 135±16 0.087DBP (mmHg; mean±SD) 81±5 81±15 0.99Serum creatinine (µmol/L; mean±SD) 102.1±41.6 91.6±35.3 0.53eGFR (ml/minute/1.73 m2; mean±SD) 74.2±26.7 92.1±28.8 0.15Serum potassium (mmol/L; mean±SD) 4.23±0.38 4.25±0.38 0.903Dose of losartan (%)25 mg 10 25 <0.00150 mg 30 58100 mg 60 17Concurrent antihypertensives (%)β-blocker 20 50Dihydropyridine CCB 30 58Diuretic 50 17α-blocker 10 8aExisting renal diseases: Not attributable to diabetes. SD: Standard deviation, DM: Diabetes mellitus, BMI: Body mass index, CAD: Coronary artery disease, IHD: Ischemic heart disease, UACR: Urinary albumin creatinine ratio, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, eGFR: Estimated glomerular filtration rate, CCB: Calcium-channel blockers359Asian J Pharm Clin Res, Vol 10, Issue 10, 2017, 357-359 Chin and Redzuan This result coincided with that discovered by Rossi et al. in the DEMAND study [14]. Other patient factors such as gender, age, and history of IHD were poorly related with UACR reduction; as opposed with what had been established previously [3,15,16].This study has highlighted the potential advantages and drawbacks of cotherapy using losartan and perindopril in treating diabetic patients with albuminuria. Nevertheless, the findings should be deduced with caution owing to several limitations such as limited sample size, sampling  bias,  and  the  existence  of  confounding  variables  (e.g.  non-standardized patient’s review date, changes in diet, medication compliance, and physical activities). Therefore, the results may not be generalizable to the entire population.CONCLUSIONOur study findings did not support the concurrent use of losartan and perindopril for the treatment of albuminuria in hypertensive diabetics population. Until the results of ongoing trials and further safety data emerge, it is recommended to withhold its use in general practice, especially  for  low  kidney-risk  patients  and  maybe  for  those  with advanced  kidney  disease.  If  used,  patients’  renal  function  should  be monitored closely, as there is no sufficient evidence of safety.REFERENCES1. Mooser V, Nussberger J, Juillerat L, Burnier M, Waeber B, Bidiville J, et al. Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol 1990;15(2):276-82.2. Rakugi H, Wang DS, Dzau VJ, Pratt RE. Potential importance of tissue angiotensin-converting enzyme inhibition in preventing neointima formation. Circulation 1994;90(1):449-55.3. National Kidney Foundation. KDOQI clinical practice guideline for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 2002;39 2 Suppl 1:S1-266.4. Pham JT, Schmitt BP, Leehey DJ. Effects of dual blockade of the renin-angiotensin system in diabetic kidney disease: A systematic review and meta-analysis. J Nephrol Ther 2012;S2:003.5. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: Effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148(1):30-48.6. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358(15):1547-9.7. Pfeffer MA, McMurray JJ, Velasquez EJ, Rouleau JL, Køber L, Maggioni AP, et al. For the valsartan in acute myocardial infarction trial investigators. Valsartan, captopril or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349(20):1839-1906.8. National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60(5):850-6.9. Clinical Trials at Villa Camozzi. Preventing ESRD in Overt Nephropathy of Type 2 Diabetes. The VALID Trial. 2012. Available from: http://www.clintrials.marionegri.it/index.php/main-trials/main-trials-ongoing/70.html. [Last accessed on 2013 Feb 25].10. Fried LF, Duckworth W, Zhang JH, O’Connor T, Brophy M, Emanuele N, et al. Design of combination angiotensin receptor blocker and angiotensin-converting enzyme inhibitor for treatment of diabetic nephropath y (VA NEPHRON-D). Clin J Am Soc Nephrol 2009;4(2):361-8.11. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, et al. Randomised controlled trial of dual blockade of reninangiotensin system in patients with hypertension, micro albuminuria, and noninsulin dependent diabetes: The Candesartan and Lisinopril Microalbuminuria (CALM) study. BMJ 2000;321(7274):1440-4.12. Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, Wang X, et al. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: Results from the ONTARGET and TRANSCEND studies. Circulation 2011;123(10):1098-7.13. Vasan RS, Larson MG, Leip EP, Evans JC, O’Donnell CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345(18):1291-7.14. Rossi MC, Nicolucci A, Pellegrini F, Comaschi M, Ceriello A, Cucinotta D, et al. Obesity and changes in urine albumin/creatinine ratio in patients with Type 2 diabetes: The DEMAND study. Nutr Metab Cardiovasc Dis 2010;20(20):110-6.15. Bildirici U, Ural E, Kilic T, Aygun F, Acar E, Cekmen M, et al. Association between documented coronary artery disease and urinary albumin, albumin to creatinine ratio. Med Sci Monit 2010;16(11):CR545-8.16. Epstein M. Aging and the kidney. J Am Soc Nephrol 1996;7(8):1106-22.Table 2: Change in UACR between losartan and losartan plus perindoprilVariable Median (IQR) Z statistic p valueLosartan alone (n=10)Losartan plus perindopril (n=12)Change in UACR  (mg/g)−38.3 (618.8) −88.4 (1105) −0.503 0.615IQR: Interquartile range, UACR: Urinary albumin creatinine ratioTable 3: Change in SBP and DBP between losartan and losartan plus perindoprilVariable Mean±SD p valueLosartan alone (n=10) Losartan plus perindopril (n=12)Change in SBP (mmHg) −10.8±16.7 −7.4±14.5 0.617Change in DBP (mmHg) −3.5±10.8 −5.8±16.2 0.695Percentage of participants achieving target BP<125/75 mmHg (%) 20 66.7 <0.001SBP: Systolic blood pressure, DBP: Diastolic blood pressure, BP: Blood pressure

EFFECT OF COMBINING LOSARTAN AND PERINDOPRIL IN DIABETIC PATIENTS WITH PROTEINURIA

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EFFECT OF COMBINING LOSARTAN AND PERINDOPRIL IN DIABETIC PATIENTS WITH PROTEINURIA

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