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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 4  |  Page : 652-659
Patterns of Anti-Hypertensive therapy in diabetic patients with and without reduced renal function


1 College of Pharmacy, Clinical Pharmacy Graduate Program, Nablus, Palestine
2 Poison Control and Drug Information Center (PCDIC), An-Najah National University, Nablus, Palestine
3 Ministry of Health, Palestinian National Authority, Jenin, Palestine

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Date of Web Publication26-Jun-2010
 

   Abstract 

Renal function deterioration is a common complication in patients with diabetes mellitus and hypertension. Appropriate use of anti-hypertensive agents and tight control of Blood Pressure (BP) can minimize and delay such complications. This study was performed in order to investigate the utilization patterns of anti-hypertensive agents and to evaluate BP control among diabetic-hypertensive patients with and without reduced renal function. In a retrospective cohort study, all diabetic­hypertensive patients attending The Al-Watani Medical Governmental Center from August 01, 2006 until August 01, 2007 were enrolled in the study. Patients with congestive heart failure and/or end­stage renal disease were excluded from the study. The proportion of use of five different anti­hypertensive drug classes were compared for all patients receiving 1, 2, 3, or 4 drugs, and separately among patients with and without reduced renal function. Over 60% of patients were receiving angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blocker (ARB), followed by diuretics (40.8%), calcium channel blockers (25.1%) and (β-blockers (12.5%). The majority of patients (> 55%) were either on mono or no drug therapy. Patients on monotherapy were mostly receiving ACEI/ARB (60%). In patients with reduced renal function, use of diuretics, but not ACEI/ARB or CCB, was higher and 41.8% of the patients were on monotherapy compared to 46.6% in patients with normal renal function. The proportion of patients achieving good BP control was 20% with mono­therapy and 28% with combination therapy. Our study suggests that the pattern of anti-hypertensive therapy was generally consistent with inter-national guidelines. Areas of improvement include in­creasing use of ACEI/ARB and diuretics, decreasing the number of untreated patients, and increasing the proportion of patients with well controlled BP in this population.

How to cite this article:
Sweileh WM, Sawalha AF, Zyoud SH, Al-Jabi SW, Tameem EJ. Patterns of Anti-Hypertensive therapy in diabetic patients with and without reduced renal function. Saudi J Kidney Dis Transpl 2010;21:652-9

How to cite this URL:
Sweileh WM, Sawalha AF, Zyoud SH, Al-Jabi SW, Tameem EJ. Patterns of Anti-Hypertensive therapy in diabetic patients with and without reduced renal function. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 Jul 21];21:652-9. Available from: http://www.sjkdt.org/text.asp?2010/21/4/652/64632

   Introduction Top


It is estimated that 2.7% of Palestinians living in the West-Bank have hypertension (HTN) and 2.1% have diabetes mellitus (DM). [1] Although, no epidemiological data are available about Palestinians who have combined DM and HTN, the prevalence of HTN, in general, is few times greater in patients with DM than in matched non-diabetic individuals. [2],[3] The major adverse outcomes of DM are a result of vas­cular complications, both, at the microvascular (retinopathy, nephropathy or neuropathy) and macrovascular levels (coronary artery disease, cerebrovascular and peripheral vascular di­sease). [4] These vascular complications are aug­mented by the co-existence of HTN. [5] To mi­nimize and delay the vascular complications among diabetic-hypertensive patients, a tight control of Blood Pressure (BP) and glucose le­vels is required. [4],[6] Although studies have indi­cated that tight blood glucose control can re­duce microvascular end-points, [7],[8],[9] no experi­mental studies have yet shown a causal rela­tionship between improved blood glucose con­trol and reduction in serious cardiovascular outcomes. In contrast, the level of control of HTN is more effective than glycemic control in reducing risk for cardiovascular and micro­vascular events and that is why, management of HTN among patients with DM should be prioritized. [10]

There are a growing number of pharmacolo­gical treatment options for patients with HTN. However, the choice of anti-hypertensive drug class is influenced by many factors such as the presence of co-morbid conditions. The seventh report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC) stated that an­giotensin converting enzyme inhibitors (ACE-I) is an important component of most regimens to control BP in diabetic patients. In those pa­tients, ACE-I may be used alone, but are much more effective when combined with thiazide­type diuretic or other anti-hypertensive drugs. [11] The JNC seventh report recommended that the BP in diabetics should be controlled to levels of 130/80 mmHg or lower. Rigorous control of BP is paramount for reducing the progression of diabetic nephropathy to end-stage renal di­sease (ESRD). In hypertensive patients with chronic kidney disease (CKD), defined as a glomerular filtration rate (GFR) < 60 mL/min, the JNC seventh report recommended a goal BP of < 130/80 mmHg and a need for using more than one anti-hypertensive drug to achieve this goal. The guidelines indicate that most pa­tients with CKD should receive an ACE-I or an angiotensin receptor blocker (ARB) in com­bination with a diuretic and that many will require a loop diuretic rather than a thiazide. [11]

The primary objectives of this study were:

  1. to evaluate the utilization of ACE-I/ARBs and other anti-hypertensive therapies re­commended by the JNC seventh report,
  2. to compare utilization of anti-hypertensive therapies for diabetic patients with, and without, reduced renal function,
  3. to investigate whether diabetic-hyperten­ sive patients with renal dysfunction receive more intensive anti-hypertensive therapy than those with normal renal function and,
  4. to assess BP control in this population.

   Methodology Top


We conducted this study at the Al-Watani Governmental Hospital and Medical Center, the largest non-surgical medical center in North Palestine with in and out-patient community medical services. Practitioners at this center include a combination of specialized and gene­ral physicians. We used the medical records of the patients to obtain diagnostic information, demographic information, laboratory test re­sults, vital signs, and prescription drug use. Data were collected retrospectively for the pe­riod August 1, 2006 to August 1, 2007. Records of all inpatients and outpatients from various clinics were screened. All aspects of the study protocol, including access to and use of the pa­tients' clinical information, were authorized by the medical ethics committee and the local health authorities. All patients with DM and HTN seen during the study period were ana­lyzed. Elevated or non-target BP was defined as greater than or equal to 130/80 mmHg, ac­cording to the JNC seventh report. [11] Reduced renal function or renal impairment was defined as creatinine clearance (Cr Cl) ≤ 60 mL/min. This cut off point was used by JNC seventh report to guide therapy for patients with CKD. Creatinine clearance was calculated using Cockcroft-Gault equation. To better study the use of ACE-I specifically for diabetes, patients During the study period, 340 diabetic-hyper­tensive patients were identified of whom, 255 met the inclusion criteria (110 males and 145 with any record of inpatient or outpatient diag­nosis of chronic heart failure (CHF) were ex­cluded. Furthermore, patients with ESRD (GFR < 15 mL/min) were excluded to avoid misinter­pretation of drug use.

Antihypertensive drug classes (β-blockers, cal­cium channel blockers, thiazide/loop diuretics, ACE-I/ARB, and α-blockers) were recorded. The number of anti-hypertensive drugs being prescribed was tabulated. We classified pa­tients with any prescriptions for ACEI or ARB as ACEI users and classified patients with any prescriptions for thiazide or loop diuretics as diuretic users. The proportion of use of these anti-hypertensive drug classes, among patients with 1, 2, 3, or 4 or more drugs, was tabulated for all patients. We present the patterns of use of anti-hypertensive drugs among all patients overall, and in sub-groups of patients on 1, 2, 3, or 4 or more drugs. We compared the pro­portions of drug class use among patients with and without renal impairment.


   Statistical Analysis Top


Chi square or Fischer's exact test, whatever appropriate, were used to test significance bet­ween categorical variables. Data were ex­pressed as mean ± SD for continuous variables and as frequency for categorical variables.


   Results Top


During the study period, 340 diabetic-hypertensive patients were identified of whom, 255 met the inclusion criteria (110 males and 145 females) and were included in the analysis. The mean age of the included patients was 64.58 ± 11.40 years. The average number of chronic diseases present among the study pa­tients was 2.83 ± 0.7 with ischemic heart di­sease (42.7%) being the most prevalent [Table 1]. The median duration of history of HTN was five years while that for DM was ten years. The most recently recorded value of systolic, diastolic BP and random blood glucose level indicated that the mean systolic BP of the patients was 151.17 ± 29.40 mmHg; diastolic BP was 86.22 ± 13.06 mmHg and the mean random blood glucose level was 257.82 ± 131.14 mg/dL. The recommended target BP of ≤ 130≤ 80 mmHg was achieved in only 61 patients (23.9%).

A total of 363 anti-hypertensive medication episodes were prescribed for the 255 patients. The average number of anti-hypertensive me­dications prescribed for the patients was 1.42 ± 0.8 (range: 0-4) and was positively correlated with the duration of DM (P< 0.001), duration of HTN (P= 0.049), and number of chronic diseases (P< 0.0001) but not with age (P= 0.16). Of the study patients, 228 (89.4%) were treated with anti-hypertensive drugs, whereas 27 (10.6%) were solely on non-pharmaco­logical interventions. Monotherapy was pres­cribed for 115 (45.09%), and combination for 113 patients (44.31%); of these, two-drug re­gimen was used in 93 (82.30%), three-drug re­gimen in 18 (15.92%), and four-drug regimen was used in two patients (1.76%) [Table 2]. Patients with controlled BP tended to use com­bination therapy more often than patients in the uncontrolled BP group (50% versus 42%), although this difference was not significant (P= 0.3). Furthermore, there was no significant difference in the overall utilization of anti­hypertensive drug classes among patients with con-trolled or uncontrolled BP. Approximately 28% of the patients on ≥ two anti-hypertensive drugs achieved control of BP while approxi­mately 20% of the patients on ≤ 1 anti-hyper­tensive drug achieved good control of BP.

The most commonly prescribed anti-hyper­tensive drug classes were ACE-I (61.5%) fol­lowed by diuretics (40.78%) and CCB (25.1%). The overall utilization of anti-hypertensive drug classes is shown in [Table 2]. Captopril (28.66%) and enalapril (66.24%) were the main types of ACE-I used. Few patients (5%) were prescribed ARB. The only two diuretics prescribed were furosemide (89.42%) and thia­zides (10.57%). Calcium channel blockers used were mainly diltiazem (54.68%) and amlodi­pine (31.25%). Monotherapy was the most co­mmon mode of therapy among the patients the patients (115, 45.09%). ACE-I was used as mo­notherapy in 69 (60%), diuretics in 27 (23.48%), CCB in 10 (8.7%) and BB in nine patients (7.8%). The two-drug combination regimen was prescribed in 93 patients with the most common combination being ACE-I with others, which were prescribed in 70 patients (75.26%).

The mean Cr Cl of the patients was 100.24 ± 73.1 mL/min; 79 patients had Cr Cl < 60 mL/ min (Group-I) and 176 patients had Cr Cl ≥ 60 mL/min (Group-II). Clinical differences bet­ween patients in Group-I and those in Group-II are shown in [Table 3]. Patients in Group-I were significantly older (67.57 ± 13.90 versus 63.24 ± 9.76 years, P= 0.014), had significantly lon­ger duration of DM (P< 0.0001) as well as higher number of chronic diseases (P< 0.017) compared to those in Group-II [Table 3], [Table 4]. The average number of anti-hypertensive medica­tions prescribed for patients in Groups-I and - II was not significantly different (1.44 versus 1.41, P = 0.8).

The pattern of anti-hypertensive medications prescribed for Groups-I and -II were studied. Patients in Group-I were prescribed a total of 114 anti-hypertensive medications, an average of 1.44 ± 0.81 medication per patient. A total of nine patients (11.4%) were on non-pharma­cologic therapy, 33 (28.7%) on monotherapy and 37 (32.7%) were on combo therapy. ACE­I was the most commonly (22.8%) prescribed drug class as monotherapy in this group of pa­tients. ACE-I with diuretics (14/79) followed by CCB with diuretic (9/79) were the most commonly prescribed 2-drug combination thera­py in Group-I patients.

In Group-II, a total of 249 anti-hypertensive medications were prescribed, an average of 1.41 ± 0.8 per patient. A total of 18/176 (10.22%) patients were on non-pharmacological therapy, 82 (46.6%) on monotherapy and 76 patients (43.18%) were on combo therapy. ACE-I (51, 28.97%) were the most commonly prescribed monotherapy drug for patients in Group-II. ACE-I with diuretics (26, 14.77%) followed by ACE-I with CCB (13, 7.4%) were the most commonly utilized 2-drug combination therapy in Group-II patients.

No significant association was seen between prescribing CCB or ACE-I and patients in either Group. However, beta blockers (P= 0.011) were significantly more prescribed to patients in Group-II, while diuretics (P= 0.016) were significantly more prescribed to patients in Group-I.

There was no significant association between patients in either Group and the use of com­bination therapy.


   Discussion Top


We investigated the patterns of anti-hyperten­sive drug therapy in diabetic-hypertensive patients with and without renal impairment. Our study revealed that more than half (55%) of the total patients was on single or no anti­hypertensive therapy. This study also showed that one-third of the total patients had reduced renal function (< 60 mL/min) suggesting that screening for renal function among diabetic­hypertensive patients and implementing rigo­rous therapy is important to delay progression to ESRD.

ACE-I was the most commonly prescribed drug class both in mono and combination the­rapy. The use of ACE-I was not significantly associated with age (≥ 65 years) or renal func­tion. The use of ACE-I among diabetic-hy­pertensive patients is in accordance with the JNC recommendations for the management of hypertension among diabetic-hypertensive pa­tients. The reported mono and combination use of ACE-I was 43.3% which is closer to that re­ported from Bahrain but less than that reported from USA in treating diabetic-hypertensive pa­tients. [12],[13] The results obtained in this study were different than those reported five years ago in Palestine. [14] In this study, we observed that there was an increase in the use of ACE-I and CCB and a decrease in the use of BB. The overall under-utilization of ACE-I could be attributed to the intolerance or adverse effects of ACE-I. In a study of patients with DM and HTN, the reported prevalence of cough asso­ciated with the use of ACE-I was 14.9%, with 4.7% of patients interrupting treatment as a result. [15] Similarly, the UKPDS Group noted that 4% of patients receiving captopril discon­tinued therapy due to cough. ARBs are consi­dered appropriate agents if patients cannot to­lerate an ACE-I. However, ARBs were rarely prescribed in this study. [16]

Diuretics ranked second when considering overall utilization of anti-hypertensive drugs and second when considering anti-hyperten­sive monotherapy. Combination of ACE-I with diuretic was the most commonly prescribed. This combination is pharmacologically favora­ble since it produces an additive anti-hyperten­sive effect and minimizes most adverse effects of either the ACE-I or the diuretics, especially hypokalemia. [17] Calcium channel blockers ranked third both in monotherapy and overall anti­hypertensive drug utilization. The non-dihydro­pyridine, diltiazem, was the most commonly prescribed CCB and verapamil was the least commonly prescribed. The dihydropyridine, ni­fedipine and amlodipine, were in between. The popularity of the non-DHP diltiazem may be due to its reported positive effects on diabetic proteinuria. [18] ACE-I plus CCB combination was not very common, although it could provide synergistic anti-hypertensive and reno-protec­tive activity, but their effects on proteinuria is comparable to ACE-I alone. [19] Non-DHP (e.g. diltiazem) plus ACE-I combination has been reported to lower insulin resistance and has an additive anti-proteinuric effect. [20]

In this study, patients with reduced renal func­tion were significantly more commonly pres­cribed diuretics than patients in Group-II. This is understandable given the fact that diabetic patients with reduced renal function are volume­expanded necessitating sodium restriction and diuretic treatment. Ideally, diabetic-hyperten­sive patients are to be treated with ACE-I plus diuretic. The importance of the diuretic agent was emphasized by the "Anti-hypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial", ALLHAT study. [21] In these pa­tients, loop diuretics are preferred. Patients with reduced renal function were prescribed combi­nation anti-hypertensive agents less frequently than patients with normal renal function. This is not in agreement with the JNC recommen­dation which emphasizes the role of combi­nation therapy in this particular category of pa­tients to delay progression to ESRD.

Similar studies conducted by a research group in Bahrain on patients with type-2 DM and HTN showed that the prescribing patterns of anti-hypertensive medications differ in many instances from the World Health Organization guidelines especially, regarding the choices and drug combinations of anti-hypertensive drugs; also, the appropriateness of anti-diabe­tic drug choice is questionable in relation to the anti-hypertensive drug used. [22]

A second study carried out in Bahrain by the same group mentioned above compared family physicians' and general practitioners' approaches to drug management of diabetic hyperten­sion. 12 In this study, the authors carried out a retrospective prescription-based study on 1266 diabetic-hypertensive patients. The authors con­cluded that there are substantial differences between family physicians and general practi­tioners in terms of preference of different drug classes for the management of diabetic-hyper­tension and that there was sub-optimal com­pliance among both family physicians and ge­neral practitioners to international recommend­dations.

We concluded from this study that there was a suboptimum use of combination therapy a­mong diabetic-hypertensive patients in general. Furthermore, diabetic-hypertensive patients with renal impairment were not given intensive anti-hypertensive therapy compared to patients with normal renal function. We recommend better drug education for health-care providers regarding appropriate and international guide­lines for this category of patients. This moni­toring can be achieved through the clinical pharmacist, whose responsibility is to deliver continuing medical education in the field of current pharmacotherapy.

 
   References Top

1.Palestinian Central Bureau of Statistics. De­tailed Statistics. Health survey 2000. Percen­tage of Persons Who Indicated Having Certain Chronic Diseases and Receiving Treatment by Disease and Selected Background Charac­teristics, 2000.  Back to cited text no. 1      
2.Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988;11:821-7.  Back to cited text no. 2  [PUBMED]    
3.Grundy SM., Benjamin IJ, Burke GL. Diabetes and cardiovascular disease. A statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134­46.  Back to cited text no. 3      
4.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylurea or insulin compared with con­ventional treatment and risk of complications in patients with type-2 diabetes mellitus (UKPDS 33). Lancet 1998;352:837-53.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]  
5.Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992;19:403-18.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]  
6.Hypertension in Diabetes Study (HDS). Prevalence hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertension 1993;11:309-17.  Back to cited text no. 6      
7.Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hyper­tension: principle results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998;351:1755-62.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]  
8.Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomized placebo­controlled trial. Lancet 2002;360:23-33.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]  
9.Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk factor intervention trial. Diabetes Care 1993;16:434-44.  Back to cited text no. 9  [PUBMED]    
10.Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hyper­tension. Systolic hypertension in Europe trial Investigators. N Engl J Med 1999;340:677-84.  Back to cited text no. 10      
11.Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, evaluation, and treatment of high blood pres­sure. National heart, lung, and blood institute; National high blood pressure education pro­gram coordinating committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42(6): 1206-52.  Back to cited text no. 11      
12.Al Khaja KA, Sequeira RP, Mathur VS, Daman­hori AH, Abdul Wahab AW. Family physi­cians' and general practitioners' approaches to drug management of diabetic hypertension in primary care. J Eval Clin Pract 2002;8(1):19-30.  Back to cited text no. 12      
13.Cooke CE, Fatodu H. Physician conformity and patient adherence to ACE inhibitors and ARBs in patients with diabetes, with and with­out renal disease and hypertension, in a medi­caid managed care organization. J Manag Care Pharm 2006;12(8):649-55  Back to cited text no. 13      
14.Sweileh WM, Aker OA, Jaradat NA. Pharma­cological and Therapeutic analysis of anti-dia­betic and antihypertensive drugs among diabetic antihypertensive patients in Palestine. J Islamic Univ Gaza (Natural Sciences Series) 2004;12 (2):35-57.  Back to cited text no. 14      
15.Malini PL, Strocchi E, Fiumi N, Ambrosioni E, Ciavarella A. ACE inhibitor-induced cough in hypertensive type 2 diabetic patients. Diabetes Care 1999;22(9):1586-7.  Back to cited text no. 15      
16.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylurea or insulin compared with con­ventional treatment and risk of complications in patients with type-2 diabetes mellitus (UKPDS 33). Lancet 1998;352:837-53.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]  
17.Ishimitsu T, Yagi S, Ebihara A, Doi Y, Domae A, Shibata A. Long term evaluation of com­bined antihypertensive therapy with lisinopril and a thiazide diuretic in patients with essen­tial hypertension. Jpn Heart J 1997;38:831­40.  Back to cited text no. 17      
18.Hoelscher D, Barkis G. Antihypertensive the­rapy and progression of diabetic renal diseases. J Cardiovasc Pharmacol 1994;23(suppl3):34-8.  Back to cited text no. 18      
19.Bakris GL, Weir MR, DeQuattro V, McMohan FG. Effects of an ACE inhibitor/calcium anta­gonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998;54:1283-9.  Back to cited text no. 19      
20.Velussi M, Brocco E, Friagato F, et al. Effects of cilazapril and amlodipine on kidney function in hypertensive NIDDM patients. Diabetes 1996;45:216-22.  Back to cited text no. 20      
21.Major outcomes in high risk hypertensive patients randomized to angiotensin-converting enzyme inhibitors or calcium channel blockers vs diuretics: The antihypertensive and Lipid­Lowering Treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97.  Back to cited text no. 21      
22.Al Khaja KA, Sequeira RP, Mathur VS. Prescribing pattern and therapeutic impli­cations for diabetic hypertension in Bahrain. Ann Pharmacother 2001;35;1350-8.  Back to cited text no. 22      

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Correspondence Address:
Waleed M Sweileh
College of Pharmacy, Clinical Pharmacology Graduate Program, An-Najah National University, Nablus
Palestine
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