I[NTRODUCTION]{.smallcaps} {#sec1-1}
==========================

*G*lobally, hypertension and Type 2 diabetes mellitus (Type 2 DM) are established risk factor for mortality, morbidity, and are well-established public health problems due to cardiovascular, kidney complications as well as self-prescribing trends in underdeveloped countries. Owing to the increasing prevalence rate, hypertension is ranked third as a major disability causing global risk.\[[@ref1][@ref2][@ref3]\] Hypertension and Type 2 DM frequently exist concomitantly.\[[@ref4]\] Etiology and disease mechanisms are common in both diseases, contributing to end-organ damage, particularly cardiovascular disease (CVD) and renal complications.\[[@ref3][@ref4][@ref5]\] Epidemiological surveys reported that more than 90% of population living an average lifespan are at increased risk of developing hypertension because of sedentary behavior, obesity, and poor dietary habits.\[[@ref6]\] Hypertension leads to 13.5% world\'s premature death, 6% disability, and about 50% glucose intolerance or hyperinsulinemia to reduce both macro- and micro-vascular complications, it is essential to achieve target blood pressure (BP).\[[@ref7][@ref8]\] It was demonstrated by clinical trials conducted with different groups of antihypertensive that control of systolic BP (SBP) to only 9--11 mmHg and diastolic BP (DBP) to 2--9 mmHg can reduce CVD events by 34%--69% and microvascular complications by 26%--46% within just 2--5 years.\[[@ref9]\]

The prevalence of hypertension together with Type 2 diabetes is increasing dramatically in Pakistani population.\[[@ref9]\] Fortunately, risk of end-organ complications can be reduced by proper management of hypertension adopting nonpharmacological (lifestyle measures) as well as pharmacological measures.\[[@ref10]\] Guidelines to manage hypertension are available nationally as well as internationally.\[[@ref10][@ref11]\] Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines (JNC-7),\[[@ref11]\] National Kidney Foundation Kidney Disease Outcomes Quality, Initiative guidelines\[[@ref12]\] as well as American Diabetes Association (ADA) guidelines\[[@ref13]\] are most current available guidelines for the treatment of hypertension. A range of antihypertensive drugs is available for hypertension management including angiotensin converting enzyme inhibitors (ACEIs), diuretics (D), beta-blockers (βBs), calcium-channel blockers (CCBs), and angiotensin receptor blockers (ARB\'s).\[[@ref14]\] Unluckily, majority of Type 2 diabetic patients (DPs) with essential hypertension do not achieve target BP and most patients with normal renal and hepatic function are in need of aggressive treatment with combination of two or three drugs from different antihypertensive classes; however, patients with concomitant complication and resistant hypertension may be in need of three or more drugs in combination. Furthermore, aggressive treatment with antihypertensive regimens from different mechanism of action is significantly effective in reducing risk of medication-related untoward effects, adverse effects on blood glucose control, and exerting protective effects on cardiac and renal functions.\[[@ref12][@ref14]\]

M[ETHODOLOGY]{.smallcaps} {#sec1-2}
=========================

Ethical approval {#sec2-1}
----------------

Ethical approval for the study was obtained from Committee of Ethics on Human Research Punjab Institute of Cardiology, Lahore, Pakistan. Vide Letter No. 24880-84.

Study design {#sec2-2}
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A prospective study of 12 weeks was conducted in Mayo Hospital, Punjab Institute of Cardiology, and National Defence Hospital, Lahore, Pakistan to evaluate efficacy and tolerability of antihypertensive drugs in Pakistani population suffering from mild to moderate hypertension in DPs as well as non-DPs (NDPs). Comprehensive case record form was designed as per objectives of the study.

Study population {#sec2-3}
----------------

Study population was selected on the basis of the prevalence of disease. Patients suffering from mild to moderate hypertension with and without Type 2 DM, both male and female, between 30 and 80 years of age were included from indoor and outdoor departments in the study. Patients with SBP above 130 mmHg and DBP above 80 mmHg were included in the study.

Inclusion criteria {#sec2-4}
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A total 430 patients, 230 "nondiabetic" and 200 DPs included in the study on the basis of prevalence of disease \[Tables [1](#T1){ref-type="table"} and [2](#T2){ref-type="table"}\]. 50% males and 50% females in "diabetic" group, 44.26% males and 51.7% females in "nondiabetic hypertensive" group, 80% nonurban and 20% urban patients in "diabetic" group, 78% nonurban and 22% urban patients in "nondiabetic hypertensive" group, 24% smoker and 76% nonsmoker in "diabetic" group, 35% smoker and 65% nonsmoker in "nondiabetic hypertensive" groups, 57% with positive family history and 43% without family history in "diabetic" group, 70% with positive family history and 30% without family history in "nondiabetic hypertensive" group participated in the study.

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Demographic presentation of patients with hypertension by age

![](JPBS-9-56-g001)

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Demographic presentation of patients with hypertension patients by weight

![](JPBS-9-56-g002)

Exclusion criteria {#sec2-5}
------------------

Patients suffering from Type 1 DM suffering from other diseases and pregnancy were excluded from the study.

Data collection tools {#sec2-6}
---------------------

Data were collected on well-designed case record form. Patients declared their willingness to participate in the study. Complete past and current medical history, physical examination, concomitant diseases, baseline BP readings were recorded in the case record form. Efficacy was monitored by recording BP reading using mercury sphygmomanometer before start of therapy as well as on weekly basis and at the end of treatment period. Tolerability of antihypertensives was assessed by monitoring effect on biochemical parameters including heart rate, blood sugar, urea, creatinine, serum electrolytes (sodium and potassium \[[Table 3](#T3){ref-type="table"}\]), bilirubin, alanine aminotransferase (ALT, uric acid), aspartate transaminase (AST), alkaline phosphatase (ALP) \[[Table 4](#T4){ref-type="table"}\], white blood cell, red blood cell, hemoglobin, platelet count, cholesterol (CHOL), triglycerides (TG), high-density lipid (HDL), low-density lipid (LDL), \[[Table 5](#T5){ref-type="table"}\]. All tests were performed by Beckman Coulter before, during, \[[Table 3](#T3){ref-type="table"}\] and at the end of study duration \[[Table 5](#T5){ref-type="table"}\].

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Safety assessment by effect on renal function

![](JPBS-9-56-g003)

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Safety assessment by effect on liver function

![](JPBS-9-56-g004)

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Safety assessment by effect on lipid profile

![](JPBS-9-56-g005)

Antihypertensive drugs used {#sec2-7}
---------------------------

Patients were assigned antihypertensive drugs in monotherapy as well as in combination using different drug classes. Classes of antihypertensive drugs used in the study were ACEI, βBs, CCBs, D, ARB\'s, and α-blocker. Drug used in the study along with their pharmacological class is given in [Table 6](#T6){ref-type="table"}.

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Drugs used in the study along with their pharmacological class

![](JPBS-9-56-g006)

Data analysis: {#sec2-8}
--------------

Data obtained were analyzed using SPSS 21.0 statistical package (IBM Corp., New York, USA). Student\'s *t*-test was used to correlate the relationship. All values were expressed as mean ± standard error and *P* ≤ 0.05 was considered statistically significant.

R[ESULTS]{.smallcaps} {#sec1-3}
=====================

80.71% nonurban, 19.28% urban patients in "diabetic group" while 78.26% nonurban, 21.74% urban patients in nondiabetic group participated in the study. Twenty percent smoker, 76% nonsmoker in "diabetic group" while 35% smoker and 65% nonsmoker in "nondiabetic group" participated in the study. 78.56% patients with +VE FH, 21.43% with −VE FH in "diabetic group" while 70.11% with +VE FH, 29.89% with −VE FH in "nondiabetic group" participated in the study.

FH = Family history, +VE = Positive, −VE = Negative.

Distribution of patients based upon drugs prescribed {#sec2-9}
----------------------------------------------------

Both diabetic and NDPs are divided into different groups on the basis of monotherapy and combination therapy \[[Table 7](#T7){ref-type="table"}\].

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Distribution of patients based upon drug prescribed

![](JPBS-9-56-g007)

D[ISCUSSION]{.smallcaps} {#sec1-4}
========================

With large number of hypertensive patients worldwide who remain uncontrolled or poorly controlled because of many factors such as sedentary lifestyle, nonavailability of proper medication, poor compliance to treatment, similar situation has been prevailing in Pakistan, and number of patients suffering from Type 2 DM together with hypertension above 30 years of age is increasing day by day, especially in rural areas, and there is clear clinical need to investigate proper, guideline based, more effective, and well-tolerated treatment regimens to achieve target BP control and to reduce major complications. Thats why keeping in view all of these factors, this study was conducted in Mayo Hospital, Punjab Institute of Cardiology, and National Defence Hospital, Lahore, Pakistan, to evaluate the efficacy and tolerability of antihypertensive drugs in diabetic and NDPs suffering from mild to moderate hypertension.\[[@ref15][@ref16][@ref17]\] In the current study, same classes of antihypertensive, that is, ACEI, CCB, βB, ARB\'s, and D \[[Table 6](#T6){ref-type="table"}\] were used in monotherapy as well as in combination therapy which were given in JNC-7.\[[@ref9][@ref15]\] ACEIs are considered preferred drug treatment in hypertensive patients with diabetes according to guidelines of ADA, NKF, WHO, JNC-VI, HOPE study.\[[@ref15][@ref16]\] In our study, majority of patients were prescribed ACEI in two, three, and four drug combinations in both diabetic and NDPs \[[Table 7](#T7){ref-type="table"}\]. In contrast to studies conducted by other researchers in other parts of world, therapy of our patients with ACEI in monotherapy as well as in combination with drugs from other classes showed significant results which are consistent with guidelines given in JNC-7.\[[@ref9][@ref15][@ref16]\] Our results showed that monotherapy with ACEI is equally effective in reducing BP both in diabetic and NDPs suffering from hypertension in contrast to previous studies which showed result only in hypertensive patients with diabetes.\[[@ref15][@ref16][@ref17][@ref18]\] Other drugs such as CCB, ARB\'s, and D were also found to be equally effective in reducing both SBP and DBP in both diabetic and NDPs, both in monotherapy as well as in combination therapy \[Tables [8](#T8){ref-type="table"} and [9](#T9){ref-type="table"}\]. In combination therapy, all drug combinations were also found to be effective in reducing SBP and DBP in both diabetic and NDPs in consistent with other previous studies.\[[@ref18][@ref19]\] In contrast to other drugs, we observed that βB showed better effects in combination therapy in comparison to monotherapy in both groups of patients. Our results are consistent but better than previous studies in achieving target levels in both diabetic and NDPs using βB in combination therapy. Similarly, CCB and ARB\'s were also found to be equally effective in reducing SBP and DBP in both diabetic and NDPs with hypertension in monotherapy as well as combination therapy \[Tables [8](#T8){ref-type="table"} and [9](#T9){ref-type="table"}\]. In contrast to ACEI, βB, CCB, and ARB\'s, it was observed that monotherapy with D resulted in better reduction of SBP in NDPs than in DPs. DBP was also reduced better in NDPs than in DPs showing that monotherapy with D is highly effective in reducing SBP and DBP in NDPs with hypertension than in DPs with hypertension \[Tables [8](#T8){ref-type="table"} and [9](#T9){ref-type="table"}\].

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Effects of drugs on systolic blood pressure

![](JPBS-9-56-g008)

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Effect of drugs on diastolic blood pressure

![](JPBS-9-56-g009)

It is clear that in our patient population, ACEI + βB reduced both SBP and DBP better than previous studies. In previous studies, it was shown that monotherapy with ACEI alone was more effective than combination of ACEI + βB.\[[@ref20][@ref21]\] Wing *et al*.\[[@ref22]\] also found that the combination of ACEI + βB is largely ineffective when compared to ACEI monotherapy,\[[@ref16][@ref22]\] but our results are inconsistent with previous studies and shown that ACEI either as monotherapy or in combination with βB is highly effective in reducing both SBP and DBP in both groups of patients that is diabetic and nondiabetic hypertensive patients \[Tables [8](#T8){ref-type="table"} and [9](#T9){ref-type="table"}\]. In contrast to previous studies, combination of ACEI with CCB has been found highly effective and exerted more significant results on SBP in NDPs than in DPs while this combination reduced DBP equally in both groups that is NDPs and DPs. Other two-drug combinations, that is, ACEI + D, CCB + ARBs, CCB+ βB, CCB + D, βB + D and βB + ARBs, and CCB + α as well as three-drug combinations were also shown to reduce BP effectively in both diabetic and NDPs and results are consistent with previous studies.\[[@ref15][@ref16]\]

Safety profile of antihypertensives in our study population was also assessed by monitoring effects of antihypertensives on biochemical parameters including urea, creatinine, uric acid, \[[Table 3](#T3){ref-type="table"}\] liver function tests (bilirubin, ALT, AST, ALP), \[[Table 4](#T4){ref-type="table"}\] and lipid profile (CHOL, TG, HDL, LDL) \[[Table 5](#T5){ref-type="table"}\]. It was observed that all antihypertensives did not cause any significant deterioration of renal, liver, and lipid functions. Renal, liver functions, and lipid profile were in normal range. Only slight difference observed was that CCB and ARB\'s either alone or in combination therapy slightly raised ALP in NDPs with hypertension than in DPs with hypertension (though within normal range) \[[Table 4](#T4){ref-type="table"}\] and ACEI and βB either alone or in combination therapy caused slightly raised ALP in DPs with hypertension than in NDPs with hypertension. Hence, on the basis of this observation, it can be suggested that CCB and ARB\'s in combination therapy are more safe in DPs with hypertension and ACEI and βB either alone or in combination therapy are more safe in NDPs with hypertension in regard of effect on ALP.\[[@ref20]\]

We also observed treatment-related side effects in both diabetic and NDPs including hyperkalemia which was caused by ARB therapy and ARB + D combination, hyperuricemia with diuretic therapy, dry cough with ACEI, leg cramping with CCB particularly in DPs, sexual dysfunction with βB, etc., ACEI caused dry cough in 75% of DPs and 55.55% of NDPs in consistent to previous studies which also confirmed the dry cough by ACEI in DPs.\[[@ref20][@ref21]\] Patients on CCB complained of pedal edema which was prevailed over using combination of CCB with diuretic exerting more significant antihypertensive effect and reducing single drug induce side effects.

Patient compliance to treatment was also assessed and good compliance to medication was reported in patients.

We conclude from above discussion that all drugs either in monotherapy or in combination are highly effective in reducing both SBP and DBP in both diabetic and NDPs and are tolerable in both diabetic and NDP.

C[ONCLUSION]{.smallcaps} {#sec1-5}
========================

Twelve-week therapy with drugs from all classes of antihypertensive either in monotherapy or combination therapy showed high BP is significantly controlled if treated under strict control and strict administration of medications. It is also clear that all combinations are according to guidelines and that long-term administration of the combination is more efficacious, safe, and well tolerated in difficult to treat subgroups of patients with hypertension. The regimen of multiple hypertensive therapies with differing mechanisms of action provides additive benefit in BP control and achievement of guideline-recommended BP goals without compromising patient safety.

Financial support and sponsorship {#sec2-10}
---------------------------------

Nil.

Conflicts of interest {#sec2-11}
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There are no conflicts of interest.

We are highly thankful to the hospital administration and all patients for their participation and valuable time.
