Utilization of Antihypertensive Drugs in Diabetic Patients in Sultan Qaboos University Hospital

Hypertension is very common among patients with diabetes. Approximately, 10 to 30% of type 1 and 60% of type 2 diabetic patients have hypertension. The patterns of utilization of antihypertensive drugs in diabetic patients were studied retrospectively in 101 hypertensive diabetic patients. Study findings focused on showing if there is any reason behind the differences. This study helps to implement interventions aimed at improving antihypertensive drug utilization and reducing medication errors. Drug factors such as dosage form, average daily dose, and adverse drug reactions were assessed. 53.5% of patients were on angiotensin II receptor blockers. 59.4% of the patients were on multiple drug therapy. Average daily dosages were almost comparable with the American Society of Hypertension and the International Society of Hypertension guidelines. Patients in the age group (≥ 60) used β -blockers with a higher percentage than patients of the age group (18-59). Vasodilators, calcium channel blockers, and β -blockers showed higher use percentages in patients with diabetic nephropathy compared to patients with no nephropathy whereas the percentage of angiotensin-converting-enzyme inhibitors was higher in no nephropathy status. 84.2% of patients had uncontrolled systolic blood pressure, and 43.6% of patients had uncontrolled diastolic blood pressure.


Introduction
Hypertension is a major worldwide health issue causing cardiovascular morbidity that affects about 26% of all adults worldwide. Hypertension is defined as a blood pressure ≥ 140/90 [1,2]. Diabetes Mellitus (DM) is an endocrine disorder. Surveys that were carried out in Oman in 2000 and 2008 found that the prevalence of T2DM was 11.1% and 9.6%, respectively [3]. It requires continuous attention to glucose monitoring, exercise, diet, and medication to achieve appropriate glycemic control [4].
Hypertension is very common among patients with diabetes.
Roughly, 10 to 30% of type 1 and 60% of type 2 diabetic patients have hypertension [5]. High blood pressure and diabetes tend to coexist together because they have common physiological traits.
High blood pressure becomes even more problematic in the setting of diabetes. Diabetes increases the quantity of fluid in the body, which tends to increase blood pressure [6]. In addition, it can decrement the distensibility of the blood vessels, increasing mean arterial pressure [7]. Furthermore, it causes changes in the way the body handles and produces insulin, which can directly raise blood pressure [8]. Appropriate reduction in blood pressure with antihypertensive agents helps to prevent diabetic microvascular and macrovascular complications [9]. Johnson and Singh found that the majority of hypertensive diabetic patients were on multidrug regimens (2005). Diabetes mellitus is now considered the most common cause of end-stage renal disease [10]. The selection of antihypertensive medications should take into consideration the kidney function status [11].
Pharmacologic management should be initiated when blood pressure is ≥ 140/90 mm Hg, irrespective of age [12]. A blood pressure value of < 130/80 mmHg was considered as good control of hypertension in hypertensive diabetic patients [13].
It was demonstrated that blood pressure control in patients with diabetes is worse than those without diabetes, and less intensive antihypertensive drug therapy is given to them [14]. The antihypertensive drugs include angiotensin-converting enzyme inhibitors (ACEI), calcium-channel blockers, angiotensin II receptor blockers (ARBs), beta blockers, diuretics and renin inhibitors [15].
In Oman, drugs available for hypertension in diabetic patients include ACEI, beta blockers, calcium channel blockers, diuretics, methyl dopa, prazosin, valsartan/hydrochlorothiazide [15]. Firstline therapy in hypertension without other compelling indications for other agents includes thiazide/thiazide like diuretics, ACEI, ARB, β-blockers, or long-acting CCBs. If blood pressure is still elevated with systolic blood pressure ≥ 20 mmHg or diastolic blood pressure ≥ 10 mmHg greater than target blood pressure, then second-line therapy is administered. Second-line therapy is comprised of combinations of first-line therapy [16]. The 2016 National Heart Foundation guidelines does not recommend β-blockers any longer as first-line agents in the management of hypertension [17]. This is reflected by the fact that two meta-analyses suggested an increased risk of stroke associated with their use [18][19][20]. Diuretics potentiate the effect of antihypertensive drugs, including calcium channel blockers. The elderly and blacks respond better to diuretics than do nonblacks and younger patients [21].
In diabetic patients, ACEI and ARB, which seem to have the potential to decrease blood glucose, may have particular benefits in preventing microalbuminuria, worsening of kidney function or other microvascular complications [22]. β-blockers and thiazide diuretics are known to reduce insulin sensitivity and transiently increase low-density lipoprotein cholesterol levels and triglycerides, whereas calcium channel blockers are metabolically neutral and angiotensin-receptor blockers, angiotensinconverting enzyme inhibitors, and renin inhibition are beneficial in increasing insulin sensitivity [23]. Selective β1-blockers are indicated in diabetic patients with ischemic heart disease without contraindications. β-blockers cannot help in renoprotection or improvement of glycemic control [24]. Drugs of choice used for the treatment of hypertension in diabetic patients with nephropathy are ACEI and ARB. ACEI, ARB, dihydropyridine calcium channel blockers (DHP-CCB) and thiazide diuretics are the drugs of choice for the treatment of hypertension in diabetic patients without nephropathy [25]. Patients with poor health literacy have little knowledge and consequently, little medication knowledge about how to manage their illness [26]. Decreased compliance with antihypertensive drugs can be affiliated to the lack of understanding of the potential benefits of treatment [27]. More interventions are required in order to improve the medical care of this category of patients [28]. A strong and consistent association between health literacy and diabetes outcomes was observed [29]. Compliance with antihypertensive drugs was higher in patients with higher cardiovascular risk. Possibly owing to increased motivation to follow the treatment course and awareness of the importance of treatment [30]. Mental illness increased the risk of non-compliance to antihypertensive drugs by 8% [31]. There is substantial agreement on the positive relationship between increased age and higher levels of compliance [32]. Treating resistant hypertension requires a rational combination of antihypertensive drugs and should include a diuretic because blood pressure lowering can lead to sodium and volume retention, which is often the cause for treatment resistance hypertension.
The prevalence of adverse drug reactions was not significantly different in women from men. Age did not predict the occurrence of side-effects nor the number of them. Patients on a diuretic reported adverse drug reactions more frequently than any other drug class. DHP-CCB decreases systemic blood pressure and raise intraglomerular capillary pressure. This is responsible for pressure-mediated glomerular injury and leads to an increase in proteinuria and faster deterioration of glomerular filtration rate [34,35]. This study was initiated to evaluate and explore the patterns of utilization of antihypertensive drugs in diabetic patients in Sultan Qaboos University Hospital (SQUH).

Aim
To identify utilization patterns of antihypertensive drugs among hypertensive diabetic patients in SQUH.

Rationale
This study is aimed at assessing the quality of antihypertensive drug use, thus ensuring effective and safe antihypertensive drug utilization. The findings of this study can be used for national comparisons of drug utilization, which will help to provide feedback to prescribers. This will help to implement interventions aimed at improving antihypertensive drug utilization and reducing medication errors.

Type of Study
A retrospective cohort study.

Patient Population
A total of 101 hypertensive diabetic patients were included in this study. pattern in order to preserve confidentiality and anonymity. The MRNs of the patients of the study were randomly selected from the session appointment lists in the Department of Endocrinology.
The time period allocated to collect patients' information was sufficient to obtain data of 5 patients per day, which is reasonable enough considering the long time needed to read the long patient history of many patients who follow up for more than 20 years.
Random sampling was used to ensure that the study sample is truly representative of the SQUH population.

Inclusion Criteria
a) Patients with diabetic hypertension. b) Age ≥ 18 years.

c)
Patients whose medications are marked as accepted status.

Exclusion Criteria
a) Patients whose medications are marked as pending status.
b) Patients whose medications are marked as discontinued status.

a) The time frame of the study patients' visits was from
February to June 2016.
b) The patients were divided into two age groups: group 1 (age: 18-59 years) and group 2 (age: ≥ 60 years). Influence factors like sex and comorbidities information were collected.

B. Blood Pressure
Value of < 130/80 mmHg was considered as good control of hypertension in diabetic patients and was used to evaluate the degree of control of hypertension in hypertensive diabetic patients. c) Medications used in each age group were reported.
Antihypertensive drug combinations of the designated drugs were identified using stacked bar charts generated from SPSS software. Drug combinations were illustrated using 101 stacked bar charts for every patient in this study. The bar charts with identical color labels meant that they were identical drug combinations, and therefore, they were omitted along with single drugs stacked bar charts. Stacked bar charts with distinct color labels were not omitted. They depicted the different drug combinations prescribed to hypertensive diabetic patients.

D. Data Analysis
The information on the data form was entered into a database

Average Daily Dose
The average daily dose was calculated for every antihypertensive drug (Table 2). Two patients used a prescribed     Table 4 shows adverse drug reactions that are directly responsible for drug discontinuation. The most common adverse drug reactions were pedal edema and dry cough. There were many cases that reported adverse reactions associated with lisinopril.

Adverse Drug Reactions of Antihypertensive Drugs
There were no reported side effects for bisoprolol, which was used by many patients.

Diabetic Patients
Antihypertensive treatment was divided into 6 drug groups     Figure 4 shows that there was a significant difference in the percentage of patients who used β-blockers (P = 0.024) in the age group (≥ 60 years) from patients of the age group (18-59 years).

Drug Groups Dispensation in Two Age Groups
There was no significant difference for the other drug groups.  Note: ★(P < 0.05) significant from patients without nephropathy.

Single Drug Therapy
Four single drugs were prescribed in hypertensive diabetic patients ( Figure 6). The drug with the highest percentage of prescriptions (48.4%) was found to be irbesartan, followed by lisinopril (41.9%). The remaining two drugs, amlodipine, and bisoprolol, were with the lowest percentages (6.5% and 3.2%, respectively) among the four drugs.

Antihypertensive Drugs Dispensation in Two Age Groups
The utilization of furosemide differed significantly (P = 0.014) in patients of age group ( ≥ 60 years) from patients of age group (18-59 years) as demonstrated in Figure 8. There was no significant difference for the other drugs. Lisinopril (P = 0.030) showed higher use percentage in patients without nephropathy (Figure 9).  Note: ★(P < 0.05) significant from patients without nephropathy.

Discussion
ARB is the most commonly prescribed drug group (53.5%), followed by diuretics (49.5%). Irbesartan (32.7%), an angiotensin II receptor blocker, had the highest use percentage in this drug group. Indapamide (12.9%) is the most frequently prescribed diuretic. These findings are consistent with recommendations from the Canadian guidelines [36] as the first-line management of hypertension in diabetic patients with chronic kidney disease is ACEI or ARB alone or in combination with another class [37].
Guidelines recommend the use of ACEI and ARB, preferably over the use of other drugs as single-drug therapy, and this reflected upon the lower utilization rates of the other antihypertensive drugs by physicians indicating good response in following evidencebased guidelines. This will ameliorate the high level of adverse drug reactions and renal failure cases.
If blood pressure is not controlled on ACEI/ARB alone, then it may be more effective to add either a CCB or a thiazide diuretic.
Although it is true that an additional drug like calcium channel blockers or a thiazide diuretic can be added, the Canadian guideline recommendations state that the combination of an ACE inhibitor or ARB, and a calcium channel blocker is the preferred and superior combination therapy regimen over the combination of ACE inhibitor or ARB, and a thiazide diuretic for hypertensive diabetic patients [38]. On the contrary, some patients in this study were prescribed ACEI or ARB with a diuretic.
Average daily dose comparisons demonstrated almost comparable dosages with ASH/ISH guidelines [39]. The high percentage of patients on multiple drug regimens indicates that many patients require at least two agents to achieve their target blood pressure. This is consistent with other studies that showed that monotherapy is inadequate in the majority of patients with hypertension. It has been estimated that 40-60% of patients will require more than one drug to achieve target blood pressure control (i.e., diastolic blood pressure < 90mm Hg) [40]. This is particularly true for patients with diabetes or chronic kidney disease, where multiple agents are required for about two-thirds of patients to achieve blood pressure < 130/80mm Hg [41]. A relatively large percentage (33.7%) of patients were on amlodipine.
In this regard, amlodipine was utilized alone in two patients  indicates that there is a high number of old patients with ischemic heart disease. This is an advantageous utilization of β-blockers in patients with ischemic heart disease but the problem lies in the fact that β-blockers can obscure the symptoms of hypoglycemia.
In this study, the most frequently reported adverse drug reaction was pedal edema. In another study, dizziness was the only adverse event seen significantly more frequently with combination therapy than with monotherapy. The large number of patients who were on amlodipine accounted for the high rate of this adverse reaction among hypertensive diabetic patients. Antihypertensive drugs implicated in causing other adverse events were also discontinued and switched to other drugs. There were many cases that reported adverse reactions associated with Lisinopril, and this explains the high utilization percentage of irbesartan compared to lisinopril.
Apparently, inappropriate prescription poses a risk of adverse drug reactions. There were no reported side effects for bisoprolol, which was used by many patients, and this could be the reason why it is highly prescribed in the elderly and nephropathy patients. A study has found that the most frequently reported antihypertensive drugs to cause adverse drug reactions in decreasing order of reports were thiazides, ACEI, and CCB, β-blockers, and ARB. One patient was on a large set of combinations consisting of 5 different antihypertensive drugs, which included indapamide, atenolol, amlodipine, hydralazine, and irbesartan.
As with any study, there were some limitations and challenges.
There are other comorbidities, which affect the prescription of antihypertensive drugs, such as chronic obstructive pulmonary disease, ischemic heart disease, and heart failure.