Research ArticleComparison of Effects of ACEIs and ARBs on Albuminuria andHyperkalemia in Indonesian Hypertensive Type 2 DiabetesMellitus Patients
Putri S Agustina1 Em Yunir2 Pukovisa Prawiroharjo 3 Johanda Damanik2
and Rani Sauriasari 1
1Faculty of Pharmacy Universitas Indonesia Depok Indonesia2Department of Internal Medicine Faculty of Medicine Universitas Indonesia Jakarta Indonesia3Department of Neurology Faculty of Medicine Universitas Indonesia Jakarta Indonesia
Correspondence should be addressed to Rani Sauriasari ranifarmasiuiacid
Received 15 November 2019 Revised 14 June 2020 Accepted 30 June 2020 Published 30 July 2020
Academic Editor Tomohiro Katsuya
Copyright copy 2020 Putri S Agustina et al +is is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited
Purpose Due to economic consideration Indonesiarsquos formulary restrictions are at odds with the treatment guidelines of theAmerican Diabetes Association (ADA) and the Eighth Joint National Committee (JNC 8) ADA and JNC 8 equally recommendthe prescription of an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) for hypertensivepatients with type 2 diabetes mellitus (T2DM) with overt proteinuria (urine albumin to creatinine ratio (UACR)ge 300mggcreatinine) However since 1 April 2018 Indonesian formulary restricted telmisartan and valsartan only for T2DM patients withdeclined renal function as shown by eGFR value +ere is no compelling evidence in favor of ACEI over ARB or vice versa exceptfor data supporting the early use of both drugs in patients with overt proteinuria However ARB is a choice if ACEIrsquos side effectsthat is coughing occurs+erefore it necessitates a detailed evaluation of the effects of ACEIs and ARBs on albuminuria and theirside effect hyperkalemia specific to Indonesian T2DM patientsMethods +is cross-sectional study involved 134 T2DM patientswhose treatment was restricted to either ACEIs (n 57) or ARBs (n 77) for at least two months before the study duringMayndashOctober 2018 Patients with known end-stage renal disease and those receiving dialysis were excluded UACR and bloodpotassium levels were compared between the two study groups Also the risk factors of albuminuria and hyperkalemia wereestimated using multivariate analysis Results T2DM patients in the ACEI and ARB groups had similar characteristics except for ahigher body mass index (p 0008) lower glomerular filtration rate (p 004) and a longer duration of prior treatment(plt 0001) in the ARB group+is study showed no differences between the ACEI and ARB groups in the proportion of cases withalbuminuria (p 097) and hyperkalemia (p 086) even after adjustment for confounders In addition uncontrolled diastolicblood pressure was a significant factor associated with albuminuria (OR 4897 95 CI 1026ndash23366 p 0046) whereas afemale was 701 less likely to develop hyperkalemia than a male (OR 0299 95 CI 0102ndash0877 p 0028) Conclusion +iscross-sectional study demonstrated that ACEIs and ARBs have a similar effect on albuminuria and hyperkalemia in Indonesianhypertensive T2DM patients even after correction for potentially confounding variables
1 Introduction
Chronic hyperglycemia in diabetes mellitus is associatedwith various complications including retinopathy neu-ropathy and nephropathy Glomerulosclerosis that isthickening of the glomerular basement membrane
glomerular hypertrophy increased proliferation of mesan-gial cells loss of podocytes and tubulointerstitial fibrosis areresponsible for impairments in kidney functioning that mayculminate in diabetic nephropathy [1] +ese cellularchanges also prompt the development of albuminuria de-clining glomerulus filtration rate increased arterial blood
HindawiInternational Journal of HypertensionVolume 2020 Article ID 5342161 8 pageshttpsdoiorg10115520205342161
pressure and increased renal flow resistance [1] Around40 of diabetic patients are reported to develop diabeticnephropathy [2] According to a survey by the IndonesianSociety of Nephrology (PERNEFRI) in 2009 125 of theIndonesian population experienced renal dysfunction due toa variety of causes such as hypertension diabetes lupus andpolycystic kidney disease [3]
Antihypertensive therapeutics inhibiting thereninndashangiotensinndashaldosterone (RAS) system such asangiotensin-converting enzyme inhibitors (ACEIs) andangiotensin receptor blockers (ARBs) are generally rec-ommended for diabetic and nondiabetic patients whenused together with calcium channel blockers and thiazidediuretics Moreover based on American Diabetes Asso-ciation ADA guidelines (2018) ACEIs and ARBs are theonly two drug classes recommended for hypertensive type2 diabetes mellitus (T2DM) patients with albuminuria toslow down the development of chronic kidney disease [4]Decreased risk of renal failure was reported in patientswith diabetic nephropathy who received ACEIs Fur-thermore the administration of the maximum tolerabledose of ACEIs reduced mortality in these patients [5]ARBs were also reported to reduce proteinuria and bloodpressure in diabetic patients with nephropathy and hy-pertension [6] +e renoprotective effects of ACEIs orARBs in diabetic patients are reflected in decreased pro-gression of macroalbuminuria and increased occurrence ofnormoalbuminuria and microalbuminuria [7] +e dif-ferent mechanisms of action of the two classes of thera-peutics might result in different renoprotective effects [8]Telmisartan an ARB acts as a partial PPAR-c agonistwhich limits inflammation induced by high glucose con-centrations in proximal tubular cells [9] Meanwhile Hsuet al reported that ACEIs provide better renoprotectiveeffects with a better safety profile than that of ARBs [10] Asingle administration of ACEIs or ARBs as the first-linetreatment reduces diabetic nephropathy progression al-though combined treatment with ACEIs and ARBs in-creases the risk of hyperkalemia without providingadditional clinical benefits [11]
Research on ACEIs and ARBs still lacks in IndonesiaSuhadi et al reported that hypertensive diabetic patientsdemonstrated no significant differences in renoprotectiveeffects between single or combined antihypertensive therapywith or without RAS inhibitors [12] A study by Helmida-nora et al showed that diabetic hypertensive patients re-ceiving either ACEIs or ARBs as antihypertensivemonotherapy did not show different renoprotective effectsas evaluated by qualitative measurements of the severityproteinuria levels [13]
American Diabetes Association (ADA) and Eighth JointNational Committee (JNC 8) equally recommend the pre-scription of ACEI or ARB for hypertensive patients withT2DM with overt proteinuria (UACRge 300mgg creati-nine) [4] However due to economic consideration for-mulary restrictions in Indonesia are at odds with thetreatment guidelines of ADA (2018) and JNC 8 Since April2018 the study location effectively adopted national for-mulary restrictions including the following
(1) All dosage forms of valsartan and telmisartan shouldbe accompanied by laboratory results showing thatthe patientrsquos estimated glomerular filtration rate(eGFR) was lt60mlmin173m2
(2) Candesartan and irbesartan administration is onlypermitted if accompanied by a written statement bythe prescribing doctor stating that the patient isresistant to ACEI [14]
+ere is no compelling evidence in favor of ACEI overARB or vice versa except for data supporting the early use ofboth drugs in patients with overt proteinuria However ARBis a choice if ACEIrsquos side effects that is coughing occursSince there has been a paucity of research on the efficacy ofACEIs and ARBs for renoprotection in Indonesian diabetichypertensive patients insufficient evidence was available tojudge whether ACEIs or ARBs might be the more effectiverenoprotective agents+erefore we conducted this researchto get more detailed comparisons of the efficacies of ACEIsand ARBs on albuminuria and also their side effecthyperkalemia specific to Indonesian T2DM patients
2 Materials and Methods
+e present preliminary cross-sectional study was conductedas part of the larger cohort study ldquoAssessment of RenalFunction and Cognitive Function in Type 2 Diabetic PatientsParameters for Decreasing Organ Functionsrdquo +is study wasconducted at RSUPN Dr Cipto Mangunkusumo HospitalJakarta Indonesia the National Referral Center for Govern-ment Hospitals in Indonesia and serves as a teaching hospital+e period of study was more than six months in 2018
21 Patients All of the participants were outpatients ofdiabetes polyclinic at the RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Diabetes was defined basedon the clinicianrsquos judgment +e minimum numbers ofparticipants were calculated by the formula
n Zα2 + Zβ1113872 1113873
2times 2σ2
micro1 minus micro2( 11138572
n (196 + 084)2 times 2(52)2
(28)2
n 54
(1)
+us the minimally required number of participants ineach treatment group was 54 patients A total of 134 type 2diabetic patients were enrolled in the study 57 of whomreceived ACEIs and 77 of whom received ARB for at leasttwo months prior the study Patients were excluded fromparticipation when diagnosed with end-stage renal disease(ESRD) when receiving dialysis treatment or corticoste-roid therapy or when taking contraceptives Finally anemicand pregnant patients were excluded from the presentstudy
2 International Journal of Hypertension
22 Study Approval and Informed Consent +is study wasreviewed and approved by the Ethics Committee of theUniversitas IndonesiandashDr Cipto Mangunkusumo Hospital(No 222UN2F1ETIK2018) and all procedures involvinghuman subjects were in accordance with the HelsinkiDeclaration of 1975 (revised in 2008) All subjects were agedover 18 years and agreed to participate in the study pro-cedures by signing an informed consent form
23 Clinical Data Collection +e collected informationincluded data on demographics socioeconomic status (ielevel of education and employment status) medical history(including a family history of diabetes obesity hyperten-sion and dyslipidemia) smoking status comorbidities andconcurrent medications and medication adherence throughthe Morisky Green and Levine (MGL) adherence ques-tionnaire [15] Patients were asked whether they were awareof their hypertensive state as well as their receiving of ACEIsor ARBs before enrolment in this study Predeterminedclinical and laboratory data included HbA1c fasting serumglucose and serum lipid profile (total cholesterol low-density lipoprotein high-density lipoprotein and triglyc-erides) which were retrieved from patientsrsquo electronicmedical records at the RSUPN Dr Cipto MangunkusumoHospital Laboratory measurements of serum creatinineserum potassium urine creatinine urine albumin and al-bumin to creatinine ratio (ACR) were obtained within threemonths before or one month after screening in the pa-thology laboratory of the RSUPN Dr CiptomangukusumoHospital+e eGFR was calculated using the CKD-EPI studyequation [4] Albuminuria was defined as UACR gt30mggcreatinine whereas hyperkalemia was defined if serumpotassium level was ge55mmolL
Blood samples were collected on the spot and urinesamples were collected early in the morning Serum creat-inine (mgdl) was determined by an ARCHITECT c8000Clinical Chemistry Analyzer (Abbot USA) ACR wasmeasured by a NycoCardtrade U-Albumin (Abbot USA)
3 Statistical Analysis
Demographic and clinical information recorded at baselinewere analyzed using IBMreg SPSSreg statistical software version23 KolmogorovndashSmirnov tests were performed to examinegroup distributions of data Continuous data were expressedin meanplusmn SD if normally distributed or median (min-max) ifnot normally distributed Categorical variables wereexpressed as frequency ranges with percentages and werecompared using chi-square tests Logistic regression multi-variate analysis with odds ratios was applied to examine theassociations between patient characteristics and treatmentoutcomes that is albuminuria and hyperkalemia Covariateswere analyzed using chi-square tests and variables withplt 025 and the variables considered relevant in the literaturewere analyzed by multivariate analysis +e selected variableswere analyzed by the binary logistic regression backwardlikelihood ratio method and the tests with p values lt 005were regarded as statistically significant
4 Results and Discussion
41 Results Of the 134 patients that met the inclusioncriteria and enrolled in this study 77 (575) patients wereon ARBs medication +e most age group in the ARB groupwas 51ndash60 years old (Figure 1) +e number of participantsin the ACEI-treated and the ARB-treated groups showedapparent differences due to the application of the inclusionand exclusion criteria However both groups met theminimum statistically required number of individuals Mostof the T2DM patients using ACEIs or ARBs were unem-ployed and were high school graduates A majority of pa-tients had been diagnosed with diabetes for more than fiveyears before Most of the patients were nonsmokers whereasonly a few of them were ex-smokers (Table 1)
Well-known crucial factors that lead to complications ofT2DM include having a long history of diabetes dyslipi-demia and elevated HbA1c levels +ese factors may con-stitute a higher risk for the development of chroniccomplications Most of the patients were found to maintainpoor glycaemic control Additionally bivariate analysis ofHbA1c levels in the ACEI and ARB groups did not showsignificant between-group differences In addition logisticregression multivariate analysis to examine associationsbetween HbA1c and treatment outcomes (albuminuria andhyperkalemia) did not show significant effects on the efficacyof the two compared drug therapies Furthermore themajority of the patients had LDL cholesterol levels above100mgdL (Table 1)
Patients received various antidiabetic agents especiallycombinations of oral diabetic drugs and insulin BesidesACEIs or ARB most of the participating patients receivedother antihypertensive drugs +e majority of patients werebeing treated with ACEIs or ARBs and one non-RAS in-hibitor as antihypertensive drugs In addition most patientshad been receiving ARBs for more than 6 months Ad-herence to treatment as evaluated by the MGL medicationadherence questionnaire showed moderate medicationadherence among the patients (Table 1) Overall mostcharacteristics of diabetic patients on ACEIs or ARBs wereequally distributed except for BMI and duration of ACEI orARB treatment
Patients with uncontrolled diastolic blood pressure hadalbuminuria more often than patients with controlled dia-stolic blood pressure (Table 2) Among female patients therewere fewer cases of albuminuria than among males(p 0068) ACEIs or ARBs treatment did not differ in theireffects on the occurrence of hyperkalemia (pgt 005) (Ta-ble 3) Among patients with moderate therapeutic adher-ence there were relatively fewer hyperkalemia cases thanamong highly adherent patients although this effect wasstatistically insignificant (p 0136) (Table 3)
42Discussion +e pathophysiology of renal dysfunction indiabetic patients develops via metabolic and hemodynamicpathways [1] +e current CKD guidelines recommend theuse of ACEIsARBs as antiproteinuric drugs despite theantihypertensive effects of both drug classes (416)
International Journal of Hypertension 3
Regardless of reducing blood pressure angiotensin 2 is moreharmful in renal dysfunction because of the constrictingability of efferent arterioles [16] Activation of the angio-tensin 2 receptor is hypothesized to antagonize detrimentaleffects of AT1 receptor activation such as increased oxi-dative stress growth factor cytokines chemokines andpreinflammation and fibrogenic mediators [16]
+e patient characteristics of the ACEI- and ARB-treatedpatients groups in this study were equal except for BMI andthe duration of RAS inhibitor treatment ARB-treated pa-tients have a larger overall BMI than ACE-treated patients+e majority of T2DM patients on ARBs received insulintreatment combined with an oral antidiabetic agent Patientswho receive insulin treatment generally report increasingbody weight [17] Body weight increments are related toinsulin therapy caused by low blood glucose concentrationthat reaches renal threshold without low-calorie intakecompensation unconscious high-calorie intake to preventhypoglycaemia and pharmacokinetic and metabolic profilesdue to subcutaneous administration [18] Differences induration of RAS inhibitor therapy in both groups show thatARB group experiences less antihypertensive therapy changethan the ACEIs group Attempts were made to minimisepotential confoundersrsquo influence by applying balanced in-clusion and exclusion criteria (eg minimising the durationof RAS inhibitor therapy and excluding patients with ESRDthose consuming corticosteroids or birth control pills pa-tients with anemia and pregnant patients) when selecting theparticipants +is allowed better control of remainingconfounding factors such as sex age smoking habit bloodpressure diabetes duration antidiabetic therapy andmedication adherence We conducted bivariate analysis toselect covariates prior to multivariate analysis Only co-variate with plt 005 in analysis with dependent variable willbe continued to multivariate logistic regression analyses
Statistical analysis shows that ACEIs or ARBs did notdiffer in albuminuria cases ((pgt 005) Table 2) Patients inthe study location received RAS inhibitors class as antihy-pertensive agents based on their diagnosis with hypertensioninstead of albuminuria +is observation is in line with theprevious meta-analysis which stated that ACEIs and ARBs
did not significantly differ in their effect to lower urinaryprotein excretion in hypertensive patients [19] Even thoughthe two drug classes affect different biochemical pathwaystheir clinical effects are similar [19] First-line therapiesprescribed for hypertensive patients include thiazide di-uretics dihydropyridine calcium channel blockers ACEIsand ARBs It is recommended to increase the dosage of thefirst drug or to add a second drug of a different class amongthe first-line recommendations if optimum blood pressurecould not be achieved or maintained +e third drug amongthe first-line recommendations is titrated two drugs com-bination could not achieve target blood pressure [20] If afterone month of treatment the optimum blood pressure cannotbe attained and maintained it is recommended to increasethe dose of the first drugs or add another drug from otherclasses in the first-line recommendations If the combinationof two drugs could not achieve target blood pressure titrate athird drug from first-line options [20] +e target of anti-hypertensive pharmacological therapy is to reduce bloodpressure or maintain blood pressure during the treatmentperiod +erefore antihypertensive agents were given basedon patientsrsquo clinical conditions A previous study supportsthe intensive decrease of blood pressure to prevent kidneyfailure so the number of antihypertensive agents increases inpatients with persistent hypertension [21] +e hypothesissupporting the intensive blood pressure lowering approachto decrease albuminuria has encouraged the medical prac-titioner to prescribe numerous antihypertensive drugs [21]Cross-sectional data highlights the prescribing pattern bythe medical practitioner in the study location +is results ina wide variety of hypertensive drugs received by the patientsbut still following the recommendation of the guidelines andnational formulary [14 20]
We observed that patients with uncontrolled diastolicblood pressure more often suffer from albuminuria thanpatients having controlled diastolic blood pressure (Table 2)+is result supports a previous study which showed thatdiastolic blood pressure above 80mmHg increases the risk ofalbuminuria [22] Other studies demonstrated that targetinglow target blood pressure (lt12070mmHg) reduces pro-teinuria even during concurrent glycaemic control strate-gies and blood pressure target 14090mmHg might be toohigh for renal protection in diabetic patients [23]
+e observation of fewer female patients with albu-minuria (Table 2) may imply a higher nitric oxide (NO)levels in female patients possibly associated with the gen-erally lower oxidative stress levels in the female [25] Highoxidative stress levels in diabetic males were related to di-abetic nephropathy progression and marked by reductionsin eGFR and increases in ACR
One of the several significant adverse events related toRAS inhibitor therapy is hyperkalemia [24] Statisticalanalysis in the present study showed that ACEI or ARBtreatment did not affect hyperkalemia (pgt 005 Table 3)Excretion dysfunction transcellular shift increase in po-tassium intake and pseudo-hyperkalemia are other factorsthat might increase serum potassium levels Hyperkalemiamediated by renal dysfunction may be due to the dys-function of one or several processes including the distant
N = 144
ACEIs (n = 57) ARBs (n = 77)
Excluded (n = 10) due toincomplete data
Figure 1 Recruitment process ACEIs angiotensin convertingenzyme inhibitors ARBs angiotensin II receptor blockers
4 International Journal of Hypertension
Table 1 Anthropometric sociodemographic lifestyle clinical and pharmacological therapy characteristics of T2DM patients on ACEIs orARBs
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
pressure and increased renal flow resistance [1] Around40 of diabetic patients are reported to develop diabeticnephropathy [2] According to a survey by the IndonesianSociety of Nephrology (PERNEFRI) in 2009 125 of theIndonesian population experienced renal dysfunction due toa variety of causes such as hypertension diabetes lupus andpolycystic kidney disease [3]
Antihypertensive therapeutics inhibiting thereninndashangiotensinndashaldosterone (RAS) system such asangiotensin-converting enzyme inhibitors (ACEIs) andangiotensin receptor blockers (ARBs) are generally rec-ommended for diabetic and nondiabetic patients whenused together with calcium channel blockers and thiazidediuretics Moreover based on American Diabetes Asso-ciation ADA guidelines (2018) ACEIs and ARBs are theonly two drug classes recommended for hypertensive type2 diabetes mellitus (T2DM) patients with albuminuria toslow down the development of chronic kidney disease [4]Decreased risk of renal failure was reported in patientswith diabetic nephropathy who received ACEIs Fur-thermore the administration of the maximum tolerabledose of ACEIs reduced mortality in these patients [5]ARBs were also reported to reduce proteinuria and bloodpressure in diabetic patients with nephropathy and hy-pertension [6] +e renoprotective effects of ACEIs orARBs in diabetic patients are reflected in decreased pro-gression of macroalbuminuria and increased occurrence ofnormoalbuminuria and microalbuminuria [7] +e dif-ferent mechanisms of action of the two classes of thera-peutics might result in different renoprotective effects [8]Telmisartan an ARB acts as a partial PPAR-c agonistwhich limits inflammation induced by high glucose con-centrations in proximal tubular cells [9] Meanwhile Hsuet al reported that ACEIs provide better renoprotectiveeffects with a better safety profile than that of ARBs [10] Asingle administration of ACEIs or ARBs as the first-linetreatment reduces diabetic nephropathy progression al-though combined treatment with ACEIs and ARBs in-creases the risk of hyperkalemia without providingadditional clinical benefits [11]
Research on ACEIs and ARBs still lacks in IndonesiaSuhadi et al reported that hypertensive diabetic patientsdemonstrated no significant differences in renoprotectiveeffects between single or combined antihypertensive therapywith or without RAS inhibitors [12] A study by Helmida-nora et al showed that diabetic hypertensive patients re-ceiving either ACEIs or ARBs as antihypertensivemonotherapy did not show different renoprotective effectsas evaluated by qualitative measurements of the severityproteinuria levels [13]
American Diabetes Association (ADA) and Eighth JointNational Committee (JNC 8) equally recommend the pre-scription of ACEI or ARB for hypertensive patients withT2DM with overt proteinuria (UACRge 300mgg creati-nine) [4] However due to economic consideration for-mulary restrictions in Indonesia are at odds with thetreatment guidelines of ADA (2018) and JNC 8 Since April2018 the study location effectively adopted national for-mulary restrictions including the following
(1) All dosage forms of valsartan and telmisartan shouldbe accompanied by laboratory results showing thatthe patientrsquos estimated glomerular filtration rate(eGFR) was lt60mlmin173m2
(2) Candesartan and irbesartan administration is onlypermitted if accompanied by a written statement bythe prescribing doctor stating that the patient isresistant to ACEI [14]
+ere is no compelling evidence in favor of ACEI overARB or vice versa except for data supporting the early use ofboth drugs in patients with overt proteinuria However ARBis a choice if ACEIrsquos side effects that is coughing occursSince there has been a paucity of research on the efficacy ofACEIs and ARBs for renoprotection in Indonesian diabetichypertensive patients insufficient evidence was available tojudge whether ACEIs or ARBs might be the more effectiverenoprotective agents+erefore we conducted this researchto get more detailed comparisons of the efficacies of ACEIsand ARBs on albuminuria and also their side effecthyperkalemia specific to Indonesian T2DM patients
2 Materials and Methods
+e present preliminary cross-sectional study was conductedas part of the larger cohort study ldquoAssessment of RenalFunction and Cognitive Function in Type 2 Diabetic PatientsParameters for Decreasing Organ Functionsrdquo +is study wasconducted at RSUPN Dr Cipto Mangunkusumo HospitalJakarta Indonesia the National Referral Center for Govern-ment Hospitals in Indonesia and serves as a teaching hospital+e period of study was more than six months in 2018
21 Patients All of the participants were outpatients ofdiabetes polyclinic at the RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Diabetes was defined basedon the clinicianrsquos judgment +e minimum numbers ofparticipants were calculated by the formula
n Zα2 + Zβ1113872 1113873
2times 2σ2
micro1 minus micro2( 11138572
n (196 + 084)2 times 2(52)2
(28)2
n 54
(1)
+us the minimally required number of participants ineach treatment group was 54 patients A total of 134 type 2diabetic patients were enrolled in the study 57 of whomreceived ACEIs and 77 of whom received ARB for at leasttwo months prior the study Patients were excluded fromparticipation when diagnosed with end-stage renal disease(ESRD) when receiving dialysis treatment or corticoste-roid therapy or when taking contraceptives Finally anemicand pregnant patients were excluded from the presentstudy
2 International Journal of Hypertension
22 Study Approval and Informed Consent +is study wasreviewed and approved by the Ethics Committee of theUniversitas IndonesiandashDr Cipto Mangunkusumo Hospital(No 222UN2F1ETIK2018) and all procedures involvinghuman subjects were in accordance with the HelsinkiDeclaration of 1975 (revised in 2008) All subjects were agedover 18 years and agreed to participate in the study pro-cedures by signing an informed consent form
23 Clinical Data Collection +e collected informationincluded data on demographics socioeconomic status (ielevel of education and employment status) medical history(including a family history of diabetes obesity hyperten-sion and dyslipidemia) smoking status comorbidities andconcurrent medications and medication adherence throughthe Morisky Green and Levine (MGL) adherence ques-tionnaire [15] Patients were asked whether they were awareof their hypertensive state as well as their receiving of ACEIsor ARBs before enrolment in this study Predeterminedclinical and laboratory data included HbA1c fasting serumglucose and serum lipid profile (total cholesterol low-density lipoprotein high-density lipoprotein and triglyc-erides) which were retrieved from patientsrsquo electronicmedical records at the RSUPN Dr Cipto MangunkusumoHospital Laboratory measurements of serum creatinineserum potassium urine creatinine urine albumin and al-bumin to creatinine ratio (ACR) were obtained within threemonths before or one month after screening in the pa-thology laboratory of the RSUPN Dr CiptomangukusumoHospital+e eGFR was calculated using the CKD-EPI studyequation [4] Albuminuria was defined as UACR gt30mggcreatinine whereas hyperkalemia was defined if serumpotassium level was ge55mmolL
Blood samples were collected on the spot and urinesamples were collected early in the morning Serum creat-inine (mgdl) was determined by an ARCHITECT c8000Clinical Chemistry Analyzer (Abbot USA) ACR wasmeasured by a NycoCardtrade U-Albumin (Abbot USA)
3 Statistical Analysis
Demographic and clinical information recorded at baselinewere analyzed using IBMreg SPSSreg statistical software version23 KolmogorovndashSmirnov tests were performed to examinegroup distributions of data Continuous data were expressedin meanplusmn SD if normally distributed or median (min-max) ifnot normally distributed Categorical variables wereexpressed as frequency ranges with percentages and werecompared using chi-square tests Logistic regression multi-variate analysis with odds ratios was applied to examine theassociations between patient characteristics and treatmentoutcomes that is albuminuria and hyperkalemia Covariateswere analyzed using chi-square tests and variables withplt 025 and the variables considered relevant in the literaturewere analyzed by multivariate analysis +e selected variableswere analyzed by the binary logistic regression backwardlikelihood ratio method and the tests with p values lt 005were regarded as statistically significant
4 Results and Discussion
41 Results Of the 134 patients that met the inclusioncriteria and enrolled in this study 77 (575) patients wereon ARBs medication +e most age group in the ARB groupwas 51ndash60 years old (Figure 1) +e number of participantsin the ACEI-treated and the ARB-treated groups showedapparent differences due to the application of the inclusionand exclusion criteria However both groups met theminimum statistically required number of individuals Mostof the T2DM patients using ACEIs or ARBs were unem-ployed and were high school graduates A majority of pa-tients had been diagnosed with diabetes for more than fiveyears before Most of the patients were nonsmokers whereasonly a few of them were ex-smokers (Table 1)
Well-known crucial factors that lead to complications ofT2DM include having a long history of diabetes dyslipi-demia and elevated HbA1c levels +ese factors may con-stitute a higher risk for the development of chroniccomplications Most of the patients were found to maintainpoor glycaemic control Additionally bivariate analysis ofHbA1c levels in the ACEI and ARB groups did not showsignificant between-group differences In addition logisticregression multivariate analysis to examine associationsbetween HbA1c and treatment outcomes (albuminuria andhyperkalemia) did not show significant effects on the efficacyof the two compared drug therapies Furthermore themajority of the patients had LDL cholesterol levels above100mgdL (Table 1)
Patients received various antidiabetic agents especiallycombinations of oral diabetic drugs and insulin BesidesACEIs or ARB most of the participating patients receivedother antihypertensive drugs +e majority of patients werebeing treated with ACEIs or ARBs and one non-RAS in-hibitor as antihypertensive drugs In addition most patientshad been receiving ARBs for more than 6 months Ad-herence to treatment as evaluated by the MGL medicationadherence questionnaire showed moderate medicationadherence among the patients (Table 1) Overall mostcharacteristics of diabetic patients on ACEIs or ARBs wereequally distributed except for BMI and duration of ACEI orARB treatment
Patients with uncontrolled diastolic blood pressure hadalbuminuria more often than patients with controlled dia-stolic blood pressure (Table 2) Among female patients therewere fewer cases of albuminuria than among males(p 0068) ACEIs or ARBs treatment did not differ in theireffects on the occurrence of hyperkalemia (pgt 005) (Ta-ble 3) Among patients with moderate therapeutic adher-ence there were relatively fewer hyperkalemia cases thanamong highly adherent patients although this effect wasstatistically insignificant (p 0136) (Table 3)
42Discussion +e pathophysiology of renal dysfunction indiabetic patients develops via metabolic and hemodynamicpathways [1] +e current CKD guidelines recommend theuse of ACEIsARBs as antiproteinuric drugs despite theantihypertensive effects of both drug classes (416)
International Journal of Hypertension 3
Regardless of reducing blood pressure angiotensin 2 is moreharmful in renal dysfunction because of the constrictingability of efferent arterioles [16] Activation of the angio-tensin 2 receptor is hypothesized to antagonize detrimentaleffects of AT1 receptor activation such as increased oxi-dative stress growth factor cytokines chemokines andpreinflammation and fibrogenic mediators [16]
+e patient characteristics of the ACEI- and ARB-treatedpatients groups in this study were equal except for BMI andthe duration of RAS inhibitor treatment ARB-treated pa-tients have a larger overall BMI than ACE-treated patients+e majority of T2DM patients on ARBs received insulintreatment combined with an oral antidiabetic agent Patientswho receive insulin treatment generally report increasingbody weight [17] Body weight increments are related toinsulin therapy caused by low blood glucose concentrationthat reaches renal threshold without low-calorie intakecompensation unconscious high-calorie intake to preventhypoglycaemia and pharmacokinetic and metabolic profilesdue to subcutaneous administration [18] Differences induration of RAS inhibitor therapy in both groups show thatARB group experiences less antihypertensive therapy changethan the ACEIs group Attempts were made to minimisepotential confoundersrsquo influence by applying balanced in-clusion and exclusion criteria (eg minimising the durationof RAS inhibitor therapy and excluding patients with ESRDthose consuming corticosteroids or birth control pills pa-tients with anemia and pregnant patients) when selecting theparticipants +is allowed better control of remainingconfounding factors such as sex age smoking habit bloodpressure diabetes duration antidiabetic therapy andmedication adherence We conducted bivariate analysis toselect covariates prior to multivariate analysis Only co-variate with plt 005 in analysis with dependent variable willbe continued to multivariate logistic regression analyses
Statistical analysis shows that ACEIs or ARBs did notdiffer in albuminuria cases ((pgt 005) Table 2) Patients inthe study location received RAS inhibitors class as antihy-pertensive agents based on their diagnosis with hypertensioninstead of albuminuria +is observation is in line with theprevious meta-analysis which stated that ACEIs and ARBs
did not significantly differ in their effect to lower urinaryprotein excretion in hypertensive patients [19] Even thoughthe two drug classes affect different biochemical pathwaystheir clinical effects are similar [19] First-line therapiesprescribed for hypertensive patients include thiazide di-uretics dihydropyridine calcium channel blockers ACEIsand ARBs It is recommended to increase the dosage of thefirst drug or to add a second drug of a different class amongthe first-line recommendations if optimum blood pressurecould not be achieved or maintained +e third drug amongthe first-line recommendations is titrated two drugs com-bination could not achieve target blood pressure [20] If afterone month of treatment the optimum blood pressure cannotbe attained and maintained it is recommended to increasethe dose of the first drugs or add another drug from otherclasses in the first-line recommendations If the combinationof two drugs could not achieve target blood pressure titrate athird drug from first-line options [20] +e target of anti-hypertensive pharmacological therapy is to reduce bloodpressure or maintain blood pressure during the treatmentperiod +erefore antihypertensive agents were given basedon patientsrsquo clinical conditions A previous study supportsthe intensive decrease of blood pressure to prevent kidneyfailure so the number of antihypertensive agents increases inpatients with persistent hypertension [21] +e hypothesissupporting the intensive blood pressure lowering approachto decrease albuminuria has encouraged the medical prac-titioner to prescribe numerous antihypertensive drugs [21]Cross-sectional data highlights the prescribing pattern bythe medical practitioner in the study location +is results ina wide variety of hypertensive drugs received by the patientsbut still following the recommendation of the guidelines andnational formulary [14 20]
We observed that patients with uncontrolled diastolicblood pressure more often suffer from albuminuria thanpatients having controlled diastolic blood pressure (Table 2)+is result supports a previous study which showed thatdiastolic blood pressure above 80mmHg increases the risk ofalbuminuria [22] Other studies demonstrated that targetinglow target blood pressure (lt12070mmHg) reduces pro-teinuria even during concurrent glycaemic control strate-gies and blood pressure target 14090mmHg might be toohigh for renal protection in diabetic patients [23]
+e observation of fewer female patients with albu-minuria (Table 2) may imply a higher nitric oxide (NO)levels in female patients possibly associated with the gen-erally lower oxidative stress levels in the female [25] Highoxidative stress levels in diabetic males were related to di-abetic nephropathy progression and marked by reductionsin eGFR and increases in ACR
One of the several significant adverse events related toRAS inhibitor therapy is hyperkalemia [24] Statisticalanalysis in the present study showed that ACEI or ARBtreatment did not affect hyperkalemia (pgt 005 Table 3)Excretion dysfunction transcellular shift increase in po-tassium intake and pseudo-hyperkalemia are other factorsthat might increase serum potassium levels Hyperkalemiamediated by renal dysfunction may be due to the dys-function of one or several processes including the distant
N = 144
ACEIs (n = 57) ARBs (n = 77)
Excluded (n = 10) due toincomplete data
Figure 1 Recruitment process ACEIs angiotensin convertingenzyme inhibitors ARBs angiotensin II receptor blockers
4 International Journal of Hypertension
Table 1 Anthropometric sociodemographic lifestyle clinical and pharmacological therapy characteristics of T2DM patients on ACEIs orARBs
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
22 Study Approval and Informed Consent +is study wasreviewed and approved by the Ethics Committee of theUniversitas IndonesiandashDr Cipto Mangunkusumo Hospital(No 222UN2F1ETIK2018) and all procedures involvinghuman subjects were in accordance with the HelsinkiDeclaration of 1975 (revised in 2008) All subjects were agedover 18 years and agreed to participate in the study pro-cedures by signing an informed consent form
23 Clinical Data Collection +e collected informationincluded data on demographics socioeconomic status (ielevel of education and employment status) medical history(including a family history of diabetes obesity hyperten-sion and dyslipidemia) smoking status comorbidities andconcurrent medications and medication adherence throughthe Morisky Green and Levine (MGL) adherence ques-tionnaire [15] Patients were asked whether they were awareof their hypertensive state as well as their receiving of ACEIsor ARBs before enrolment in this study Predeterminedclinical and laboratory data included HbA1c fasting serumglucose and serum lipid profile (total cholesterol low-density lipoprotein high-density lipoprotein and triglyc-erides) which were retrieved from patientsrsquo electronicmedical records at the RSUPN Dr Cipto MangunkusumoHospital Laboratory measurements of serum creatinineserum potassium urine creatinine urine albumin and al-bumin to creatinine ratio (ACR) were obtained within threemonths before or one month after screening in the pa-thology laboratory of the RSUPN Dr CiptomangukusumoHospital+e eGFR was calculated using the CKD-EPI studyequation [4] Albuminuria was defined as UACR gt30mggcreatinine whereas hyperkalemia was defined if serumpotassium level was ge55mmolL
Blood samples were collected on the spot and urinesamples were collected early in the morning Serum creat-inine (mgdl) was determined by an ARCHITECT c8000Clinical Chemistry Analyzer (Abbot USA) ACR wasmeasured by a NycoCardtrade U-Albumin (Abbot USA)
3 Statistical Analysis
Demographic and clinical information recorded at baselinewere analyzed using IBMreg SPSSreg statistical software version23 KolmogorovndashSmirnov tests were performed to examinegroup distributions of data Continuous data were expressedin meanplusmn SD if normally distributed or median (min-max) ifnot normally distributed Categorical variables wereexpressed as frequency ranges with percentages and werecompared using chi-square tests Logistic regression multi-variate analysis with odds ratios was applied to examine theassociations between patient characteristics and treatmentoutcomes that is albuminuria and hyperkalemia Covariateswere analyzed using chi-square tests and variables withplt 025 and the variables considered relevant in the literaturewere analyzed by multivariate analysis +e selected variableswere analyzed by the binary logistic regression backwardlikelihood ratio method and the tests with p values lt 005were regarded as statistically significant
4 Results and Discussion
41 Results Of the 134 patients that met the inclusioncriteria and enrolled in this study 77 (575) patients wereon ARBs medication +e most age group in the ARB groupwas 51ndash60 years old (Figure 1) +e number of participantsin the ACEI-treated and the ARB-treated groups showedapparent differences due to the application of the inclusionand exclusion criteria However both groups met theminimum statistically required number of individuals Mostof the T2DM patients using ACEIs or ARBs were unem-ployed and were high school graduates A majority of pa-tients had been diagnosed with diabetes for more than fiveyears before Most of the patients were nonsmokers whereasonly a few of them were ex-smokers (Table 1)
Well-known crucial factors that lead to complications ofT2DM include having a long history of diabetes dyslipi-demia and elevated HbA1c levels +ese factors may con-stitute a higher risk for the development of chroniccomplications Most of the patients were found to maintainpoor glycaemic control Additionally bivariate analysis ofHbA1c levels in the ACEI and ARB groups did not showsignificant between-group differences In addition logisticregression multivariate analysis to examine associationsbetween HbA1c and treatment outcomes (albuminuria andhyperkalemia) did not show significant effects on the efficacyof the two compared drug therapies Furthermore themajority of the patients had LDL cholesterol levels above100mgdL (Table 1)
Patients received various antidiabetic agents especiallycombinations of oral diabetic drugs and insulin BesidesACEIs or ARB most of the participating patients receivedother antihypertensive drugs +e majority of patients werebeing treated with ACEIs or ARBs and one non-RAS in-hibitor as antihypertensive drugs In addition most patientshad been receiving ARBs for more than 6 months Ad-herence to treatment as evaluated by the MGL medicationadherence questionnaire showed moderate medicationadherence among the patients (Table 1) Overall mostcharacteristics of diabetic patients on ACEIs or ARBs wereequally distributed except for BMI and duration of ACEI orARB treatment
Patients with uncontrolled diastolic blood pressure hadalbuminuria more often than patients with controlled dia-stolic blood pressure (Table 2) Among female patients therewere fewer cases of albuminuria than among males(p 0068) ACEIs or ARBs treatment did not differ in theireffects on the occurrence of hyperkalemia (pgt 005) (Ta-ble 3) Among patients with moderate therapeutic adher-ence there were relatively fewer hyperkalemia cases thanamong highly adherent patients although this effect wasstatistically insignificant (p 0136) (Table 3)
42Discussion +e pathophysiology of renal dysfunction indiabetic patients develops via metabolic and hemodynamicpathways [1] +e current CKD guidelines recommend theuse of ACEIsARBs as antiproteinuric drugs despite theantihypertensive effects of both drug classes (416)
International Journal of Hypertension 3
Regardless of reducing blood pressure angiotensin 2 is moreharmful in renal dysfunction because of the constrictingability of efferent arterioles [16] Activation of the angio-tensin 2 receptor is hypothesized to antagonize detrimentaleffects of AT1 receptor activation such as increased oxi-dative stress growth factor cytokines chemokines andpreinflammation and fibrogenic mediators [16]
+e patient characteristics of the ACEI- and ARB-treatedpatients groups in this study were equal except for BMI andthe duration of RAS inhibitor treatment ARB-treated pa-tients have a larger overall BMI than ACE-treated patients+e majority of T2DM patients on ARBs received insulintreatment combined with an oral antidiabetic agent Patientswho receive insulin treatment generally report increasingbody weight [17] Body weight increments are related toinsulin therapy caused by low blood glucose concentrationthat reaches renal threshold without low-calorie intakecompensation unconscious high-calorie intake to preventhypoglycaemia and pharmacokinetic and metabolic profilesdue to subcutaneous administration [18] Differences induration of RAS inhibitor therapy in both groups show thatARB group experiences less antihypertensive therapy changethan the ACEIs group Attempts were made to minimisepotential confoundersrsquo influence by applying balanced in-clusion and exclusion criteria (eg minimising the durationof RAS inhibitor therapy and excluding patients with ESRDthose consuming corticosteroids or birth control pills pa-tients with anemia and pregnant patients) when selecting theparticipants +is allowed better control of remainingconfounding factors such as sex age smoking habit bloodpressure diabetes duration antidiabetic therapy andmedication adherence We conducted bivariate analysis toselect covariates prior to multivariate analysis Only co-variate with plt 005 in analysis with dependent variable willbe continued to multivariate logistic regression analyses
Statistical analysis shows that ACEIs or ARBs did notdiffer in albuminuria cases ((pgt 005) Table 2) Patients inthe study location received RAS inhibitors class as antihy-pertensive agents based on their diagnosis with hypertensioninstead of albuminuria +is observation is in line with theprevious meta-analysis which stated that ACEIs and ARBs
did not significantly differ in their effect to lower urinaryprotein excretion in hypertensive patients [19] Even thoughthe two drug classes affect different biochemical pathwaystheir clinical effects are similar [19] First-line therapiesprescribed for hypertensive patients include thiazide di-uretics dihydropyridine calcium channel blockers ACEIsand ARBs It is recommended to increase the dosage of thefirst drug or to add a second drug of a different class amongthe first-line recommendations if optimum blood pressurecould not be achieved or maintained +e third drug amongthe first-line recommendations is titrated two drugs com-bination could not achieve target blood pressure [20] If afterone month of treatment the optimum blood pressure cannotbe attained and maintained it is recommended to increasethe dose of the first drugs or add another drug from otherclasses in the first-line recommendations If the combinationof two drugs could not achieve target blood pressure titrate athird drug from first-line options [20] +e target of anti-hypertensive pharmacological therapy is to reduce bloodpressure or maintain blood pressure during the treatmentperiod +erefore antihypertensive agents were given basedon patientsrsquo clinical conditions A previous study supportsthe intensive decrease of blood pressure to prevent kidneyfailure so the number of antihypertensive agents increases inpatients with persistent hypertension [21] +e hypothesissupporting the intensive blood pressure lowering approachto decrease albuminuria has encouraged the medical prac-titioner to prescribe numerous antihypertensive drugs [21]Cross-sectional data highlights the prescribing pattern bythe medical practitioner in the study location +is results ina wide variety of hypertensive drugs received by the patientsbut still following the recommendation of the guidelines andnational formulary [14 20]
We observed that patients with uncontrolled diastolicblood pressure more often suffer from albuminuria thanpatients having controlled diastolic blood pressure (Table 2)+is result supports a previous study which showed thatdiastolic blood pressure above 80mmHg increases the risk ofalbuminuria [22] Other studies demonstrated that targetinglow target blood pressure (lt12070mmHg) reduces pro-teinuria even during concurrent glycaemic control strate-gies and blood pressure target 14090mmHg might be toohigh for renal protection in diabetic patients [23]
+e observation of fewer female patients with albu-minuria (Table 2) may imply a higher nitric oxide (NO)levels in female patients possibly associated with the gen-erally lower oxidative stress levels in the female [25] Highoxidative stress levels in diabetic males were related to di-abetic nephropathy progression and marked by reductionsin eGFR and increases in ACR
One of the several significant adverse events related toRAS inhibitor therapy is hyperkalemia [24] Statisticalanalysis in the present study showed that ACEI or ARBtreatment did not affect hyperkalemia (pgt 005 Table 3)Excretion dysfunction transcellular shift increase in po-tassium intake and pseudo-hyperkalemia are other factorsthat might increase serum potassium levels Hyperkalemiamediated by renal dysfunction may be due to the dys-function of one or several processes including the distant
N = 144
ACEIs (n = 57) ARBs (n = 77)
Excluded (n = 10) due toincomplete data
Figure 1 Recruitment process ACEIs angiotensin convertingenzyme inhibitors ARBs angiotensin II receptor blockers
4 International Journal of Hypertension
Table 1 Anthropometric sociodemographic lifestyle clinical and pharmacological therapy characteristics of T2DM patients on ACEIs orARBs
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
Regardless of reducing blood pressure angiotensin 2 is moreharmful in renal dysfunction because of the constrictingability of efferent arterioles [16] Activation of the angio-tensin 2 receptor is hypothesized to antagonize detrimentaleffects of AT1 receptor activation such as increased oxi-dative stress growth factor cytokines chemokines andpreinflammation and fibrogenic mediators [16]
+e patient characteristics of the ACEI- and ARB-treatedpatients groups in this study were equal except for BMI andthe duration of RAS inhibitor treatment ARB-treated pa-tients have a larger overall BMI than ACE-treated patients+e majority of T2DM patients on ARBs received insulintreatment combined with an oral antidiabetic agent Patientswho receive insulin treatment generally report increasingbody weight [17] Body weight increments are related toinsulin therapy caused by low blood glucose concentrationthat reaches renal threshold without low-calorie intakecompensation unconscious high-calorie intake to preventhypoglycaemia and pharmacokinetic and metabolic profilesdue to subcutaneous administration [18] Differences induration of RAS inhibitor therapy in both groups show thatARB group experiences less antihypertensive therapy changethan the ACEIs group Attempts were made to minimisepotential confoundersrsquo influence by applying balanced in-clusion and exclusion criteria (eg minimising the durationof RAS inhibitor therapy and excluding patients with ESRDthose consuming corticosteroids or birth control pills pa-tients with anemia and pregnant patients) when selecting theparticipants +is allowed better control of remainingconfounding factors such as sex age smoking habit bloodpressure diabetes duration antidiabetic therapy andmedication adherence We conducted bivariate analysis toselect covariates prior to multivariate analysis Only co-variate with plt 005 in analysis with dependent variable willbe continued to multivariate logistic regression analyses
Statistical analysis shows that ACEIs or ARBs did notdiffer in albuminuria cases ((pgt 005) Table 2) Patients inthe study location received RAS inhibitors class as antihy-pertensive agents based on their diagnosis with hypertensioninstead of albuminuria +is observation is in line with theprevious meta-analysis which stated that ACEIs and ARBs
did not significantly differ in their effect to lower urinaryprotein excretion in hypertensive patients [19] Even thoughthe two drug classes affect different biochemical pathwaystheir clinical effects are similar [19] First-line therapiesprescribed for hypertensive patients include thiazide di-uretics dihydropyridine calcium channel blockers ACEIsand ARBs It is recommended to increase the dosage of thefirst drug or to add a second drug of a different class amongthe first-line recommendations if optimum blood pressurecould not be achieved or maintained +e third drug amongthe first-line recommendations is titrated two drugs com-bination could not achieve target blood pressure [20] If afterone month of treatment the optimum blood pressure cannotbe attained and maintained it is recommended to increasethe dose of the first drugs or add another drug from otherclasses in the first-line recommendations If the combinationof two drugs could not achieve target blood pressure titrate athird drug from first-line options [20] +e target of anti-hypertensive pharmacological therapy is to reduce bloodpressure or maintain blood pressure during the treatmentperiod +erefore antihypertensive agents were given basedon patientsrsquo clinical conditions A previous study supportsthe intensive decrease of blood pressure to prevent kidneyfailure so the number of antihypertensive agents increases inpatients with persistent hypertension [21] +e hypothesissupporting the intensive blood pressure lowering approachto decrease albuminuria has encouraged the medical prac-titioner to prescribe numerous antihypertensive drugs [21]Cross-sectional data highlights the prescribing pattern bythe medical practitioner in the study location +is results ina wide variety of hypertensive drugs received by the patientsbut still following the recommendation of the guidelines andnational formulary [14 20]
We observed that patients with uncontrolled diastolicblood pressure more often suffer from albuminuria thanpatients having controlled diastolic blood pressure (Table 2)+is result supports a previous study which showed thatdiastolic blood pressure above 80mmHg increases the risk ofalbuminuria [22] Other studies demonstrated that targetinglow target blood pressure (lt12070mmHg) reduces pro-teinuria even during concurrent glycaemic control strate-gies and blood pressure target 14090mmHg might be toohigh for renal protection in diabetic patients [23]
+e observation of fewer female patients with albu-minuria (Table 2) may imply a higher nitric oxide (NO)levels in female patients possibly associated with the gen-erally lower oxidative stress levels in the female [25] Highoxidative stress levels in diabetic males were related to di-abetic nephropathy progression and marked by reductionsin eGFR and increases in ACR
One of the several significant adverse events related toRAS inhibitor therapy is hyperkalemia [24] Statisticalanalysis in the present study showed that ACEI or ARBtreatment did not affect hyperkalemia (pgt 005 Table 3)Excretion dysfunction transcellular shift increase in po-tassium intake and pseudo-hyperkalemia are other factorsthat might increase serum potassium levels Hyperkalemiamediated by renal dysfunction may be due to the dys-function of one or several processes including the distant
N = 144
ACEIs (n = 57) ARBs (n = 77)
Excluded (n = 10) due toincomplete data
Figure 1 Recruitment process ACEIs angiotensin convertingenzyme inhibitors ARBs angiotensin II receptor blockers
4 International Journal of Hypertension
Table 1 Anthropometric sociodemographic lifestyle clinical and pharmacological therapy characteristics of T2DM patients on ACEIs orARBs
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
Table 1 Anthropometric sociodemographic lifestyle clinical and pharmacological therapy characteristics of T2DM patients on ACEIs orARBs
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
nephron flow rate the intensity of aldosterone secretion andpotassium secretion pathways [25] Female patients werefound to present with hyperkalemia less often than males(plt 003 Table 3) +is result supports past research that
females have lower potassium concentration than males[26]
Patients with moderate medication adherence havefewer hyperkalemia cases than patients with highmedication
Table 1 Continued
Characteristics ACEIs ARBsp valueN 57 (425) N 77 (575)
plt 0001blowastle3 months 23 (404) 5 (65)3ndash6 months 9 (158) 9 (117)gt6 months 25 (438) 63 (818)ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers ACR albumin to creatinine ratio eGFR estimated glomerularfiltration rate (CKD-EPI equation) aContinuity correction bPearson chi-square cindependent t-test dMannndashWhitney test denominator for each char-acteristic is number in respective groups categorical data presented as n () continuous data presented in meanplusmn SD or median (min-max) lowaststatisticallysignificant
Table 2 Factors affecting the cases of albuminuria in T2DM patients on ACEIs or ARBs
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
adherence but not significant (p 0136 Table 3) Medi-cation adherence in this study was related to the patientrsquosadherence to both antidiabetic and antihypertensive treat-ments Low medication adherence is known to lead toimpaired glycaemic and blood pressure control and in-creases the incidence of adverse events [27 28] Patients withuncontrolled systolic blood pressure less often showhyperkalemia than patients with better control (p 0103Table 3) +is result shows that routine use of medicationmay increase hyperkalemia in T2DM patients on ACEIs orARBs
Overall the results of the present study showed that sexand diastolic blood pressure control affect the number ofalbuminuria cases whereas sex systolic blood pressurecontrol and medication adherence affect the number ofcases of hyperkalemia
+e present study had a cross-sectional design thatdoes not allow far-reaching recommendations about thelongitudinal effects of the examined treatments Futurecohort studies will be needed to address these issues Wewould suggest a more extensive data collection regardingsmoking habits increasing the number of patientsrecruited and recruitment of patients from multiple lo-cations Nevertheless the present study provided initialinsights into the effects of ACEIs versus ARBs on albu-minuria and hyperkalemia in hypertensive T2DMpatients
5 Conclusions
+is research demonstrates that treatments with ACEIs andARBs have similar effects on albuminuria and hyperkalemiawhether confounding variables are corrected for or not
Data Availability
+e data used in the study are available upon request to thecorresponding author
Conflicts of Interest
+e authors claim no conflicts of interest while preparingconducting or reporting this study
Acknowledgments
+e authors would like to thank RSUPN Dr Cipto Man-gunkusumo Hospital Jakarta Indonesia for help andsupport during the performance of this study +e authorswould like to thank Professor Sudibyo Supardi PhD anepidemiologist at the National Institute of Health Researchand Development Ministry of Health Indonesia JakartaIndonesia for helping them to analyze the data +is studywas supported by a PDUPT grant of the Ministry of Re-search Technology and Higher Education Indonesia forfinancial support (no 0045E3LL2018)
Table 3 Factors affecting the cases of hyperkalemia in T2DM patients on ACEIs or ARBs
RAS renin-angiotensin-aldosterone system ACEIs angiotensin converting enzyme inhibitors ARBs angiotensin II receptor blockers lowastStatisticallysignificant
International Journal of Hypertension 7
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
8 International Journal of Hypertension
References
[1] M K Arora and U K Singh ldquoMolecular mechanisms in thepathogenesis of diabetic nephropathy an updaterdquo VascularPharmacology vol 58 no 4 pp 259ndash271 2013
[2] American Diabetes Association ldquoStandard of medical care indiabetes-2017rdquoDiabetes Care vol 40 no 1 pp s4ndashs128 2017
[3] Pernefri ldquoReport of Indonesian renal registry (IRR)rdquo vol 8pp 1ndash45 2015
[4] KDIGO ldquoEvaluation and management of chronic kidney dis-easerdquoKidney International vol 3 no1 p 9 2013 httpskdigoorgwp-contentuploads201702KDIGO_2012_CKD_GLpdf
[5] G F M Strippoli C Bonifati M Craig S D Navaneethanand J C Craig ldquoAngiotensin converting enzyme inhibitorsand angiotensin II receptor antagonists for preventing theprogression of diabetic kidney diseaserdquo Cochrane DatabaseSystemic Review vol 4 Article ID CD006257 2006
[6] G Bakris E Burgess M Weir G Davidai and S KovalldquoTelmisartan is more effective than losartan in reducingproteinuria in patients with diabetic nephropathyrdquo KidneyInternational vol 74 no 3 pp 364ndash369 2008
[7] A J Farmer R Stevens J Hirst et al ldquoOptimal strategies foridentifying kidney disease in diabetes properties of screeningtests progression of renal dysfunction and impact of treat-ment-systematic review and modelling of progression andcost-effectivenessrdquo Health Technology Assessment vol 18no 14 pp 1ndash128 2014
[8] A H Barnett S C Bain P Bouter et al ldquoAngiotensin-re-ceptor blockade versus converting-enzyme inhibition in type2 diabetes and nephropathyrdquo New England Journal of Med-icine vol 351 no 19 pp 1952ndash1961 2004
[9] P Bichu R Nistala A Khan J R Sowers A Whaley-Connellet al ldquoAngiotensin receptor blockers for the reduction ofproteinuria in diabetic patients with overt nephropathy re-sultsrdquo Vascular Health Risk Management vol 5 no 573pp 129ndash140 2009
[10] F Hsu F Lin C Wang H Ou and S Huang ldquoRenopro-tective effect of angiotensin-converting enzyme inhibitors andangiotensin II receptor blockers in diabetic patients withproteinuriardquo vol 10050 no 33 pp 358ndash368 2017
[11] E Vivian and C Mannebach ldquo+erapeutic approaches toslowing the progression of diabetic nephropathy-is less bestrdquoDrugs in Context pp 1ndash12 2013
[12] R Suhadi I A Donatus and B Sidarto ldquoEvaluasi penggu-naan antihipertensi sistem angiotensin renin untuk melin-dungi ginjal pada pasien diabetes di rumah sakit X Yogyakarta[Evaluation of using antihipertensin of angiotensin reninsystem to kidney protection on diabetic patient in X hospitalof Yogyakarta]rdquo Majalah Farmasi Indonesia vol 15 no 4pp 177ndash184 2004 httpsindonesianjpharmfarmasiugmacidindexphp3articleview577452
[13] R Helmidanora and I D P Pramantara PerbandinganPencapaian Target Tekanan Darah dan Renoprotektif padaMonoterapi ACEIs dan ARBs di RSUD Samarinda UniversitasGadjah Mada Yogyakarta Indonesia 2015
[14] N F Moeloek Keputusan Menteri Kesehatan RI NoHK0107MENKES6592017 Tentang FormulariumNasional Keputusan Menteri Kesehatan Republik IndonesiaDaegu Indonesia 2017
[15] D E Morisky L W Green and D M Levines ldquoConcurrentand predictive validity of a self-reported measure of medi-cation adherencerdquo Medical Care vol 24 no 1 pp 67ndash742016
[16] K A Griffin and A K Bidani ldquoAngiotensin II type 2 receptorin chronic kidney disease the good side of angiotensin IIrdquoKidney International vol 75 no 10 pp 1006ndash1008 2009
[17] American Diabetes Association ldquoStandard medical care indiabetes 2018rdquo Diabetes Care vol 41 no 1 2018 httpdiabetesednetwp-contentuploads2012172018-ADA-Standards-of-Carepdf
[18] D Russell-Jones and R Khan ldquoInsulin-associated weight gainin diabetes - causes effects and coping strategiesrdquo DiabetesObesity and Metabolism vol 9 no 6 pp 799ndash812 2007
[19] R Xu S Sun Y Huo et al ldquoEffects of ACEIs versus ARBs onproteinuria or albuminuria in primary hypertension a meta-analysis of randomized trialsrdquo Medicine (Baltimore) vol 94no 39 p e1560 2015
[20] P A James S Oparil B L Carter et al ldquoEvidence-basedguideline for the management of high blood pressure inadultsrdquo Journal of International Medicine Taiwan vol 25no 3 pp 165ndash175 2014
[21] J Lv P Ehteshami M J Sarnak et al ldquoEffects of intensiveblood pressure lowering on the progression of chronic kidneydisease a systematic review and meta-analysisrdquo CanadianMedical Association Journal vol 185 no 11 pp 941-9422013
[22] C-S Sheng M Liu J Zou Q-F Huang Y Li andJ-G Wang ldquoAlbuminuria in relation to the single andcombined effects of systolic and diastolic blood pressure inChineserdquo Blood Pressure vol 22 no 3 pp 158ndash164 2013
[23] E Ku C E McCulloch M Mauer S E GitelmanB A Grimes and C-Y Hsu ldquoAssociation between bloodpressure and adverse renal events in type 1 diabetesrdquoDiabetesCare vol 39 no 12 pp 2218ndash2224 2016
[24] B F Palmer ldquoManaging hyperkalemia caused by inhibitors ofthe renin-angiotensin-aldosterone systemrdquo New EnglandJournal of Medicine vol 351 no 6 pp 585ndash592 2004
[25] A J Viera and NWouk ldquoPotassium disorders hypokalaemiaand hyperkalemiardquo American Family Physician vol 92 no 6pp 487ndash495 2015
[26] D K Wysowski C Kornegay P Nourjah and A TrontellldquoSex and age differences in serum potassium in the UnitedStatesrdquo Clinical Chemistry vol 49 no 1 pp 190ndash192 2003
[27] C D Kang P P M Tsang W T L Li et al ldquoDeterminants ofmedication adherence and blood pressure control amonghypertensive patients in Hong Kong a cross-sectional studyrdquoInternational Journal of Cardiology vol 182 pp 250ndash2572015
[28] D M Mosen H Glauber A B Stoneburner andA C Feldstein ldquoAssessing the association between medica-tion adherence and glycaemic controlrdquo American Journal ofPharmacological Benefits vol 9 no 3 pp 82ndash88 2017 httpsajpblives3amazonawscom_media_pdfAJPB_0506_2017_Mosen (final)pdf
