Gender-based treatment outcomes in diabetic hypertensionAHH Damanhori1, KAJ Al Khaja2, RP Sequeira2
1 Primary Care, Ministry of Health Manama, Manama, Bahrain
2 Department of Pharmacology and Therapeutics, Arabian Gulf University, Manama, Bahrain
Background: In developing countries, gender-based treatment disparities in cardiovascular preventive therapy have received little attention. Aims: To evaluate the gender-based differences in cardiovascular disease risk profile, drug prescribing pattern, and blood pressure (BP) and glycemic control rates in diabetic hypertensives treated at primary care setting in Bahrain. Settings and Design: A retrospective study at primary care setting. Materials and Methods: An audit of the medical records of 392 diabetic hypertensives (127 men, 265 women). Results: BP and glycemic targets were achieved in <10% and <13% of diabetic hypertensives, respectively. Angiotensin converting enzyme inhibitors monotherapy was more often prescribed in males. Apart from this, no significant differences in prescribing pattern were observed between male and female diabetic hypertensives treated with either antihypertensive mono or multidrug therapies. With the exception of insulin which was more often prescribed to females, a similar prescribing pattern and rank order of antidiabetics, either as monotherapy or combinations, was observed in both genders. The majority of diabetic hypertensives were at high cardiovascular risk. The body mass index and total cholesterol level were greater in females. Prescribing lipid-lowering drugs and aspirin were suboptimal; aspirin was more often prescribed to males. There was no gender-based difference with regard to the use of lipid-lowering drugs. Conclusions: BP and glycemic controls were suboptimal in both male and female diabetic hypertensives treated by primary care physicians. Cardiovascular disease preventive strategies have received little attention regardless of gender or other risk factors. Gender-based treatment inequities also need to be addressed.
Keywords: Blood pressure control, cardiovascular preventive therapy, cardiovascular risk factors, gender-based treatment disparities, glycemic control, primary care in developing countries
The classic cardiovascular risk factors are consistent and common but are largely undertreated and uncontrolled in many regions of the world , and result in high rate of cardiovascular events.  Hypertension is extremely common in patients with type 2 diabetes  and the co-existence of hypertension and diabetes increases the risk of macrovascular and microvascular complications.  These complications are significantly reduced by optimal control of blood pressure (BP). ,, The primary goal of antihypertensive treatment in patients with diabetes is to lower BP, whenever possible, below 130/85 mm Hg.  Effective and complementary combinations of two or more antihypertensives are often needed to achieve the target BP goal in diabetic patients. ,,,,
Low-dose aspirin is considered as a primary prevention strategy in high-risk diabetics to reduce adverse clinical outcomes,  especially of major cardiovascular events. , Lipid-lowering therapy results in greater reduction in the rate of coronary events in diabetic subjects than in nondiabetic ones. , Patients with type 2 diabetes without prior myocardial infarction (MI) have a risk of infarction similar to that among nondiabetic patients with a prior MI suggesting that all persons with diabetes should be treated with lipid-lowering agents as if they had prior coronary heart diseases. 
Gender considerations are important in pathophysiology and treatment of hypertension, and gender-related adverse effects of antihypertensives may limit the choice of drug therapy. Hypertension during pregnancy, use of oral contraceptives, menopause and estrogen replacement therapy may influence the BP regulation in ways that have therapeutic implications for some women. 
Recent studies from developed countries have addressed gender differences in control of hypertension, diabetes, and other cardiovascular risk factors in diabetic hypertensive patients. ,,, In this primary-care based study from a developing country, Bahrain, the gender-based differences in cardiovascular risk factor profile (including risk prevention treatment), drug prescribing pattern, and BP and glycemic control rates in patients with hypertension and type 2 diabetes mellitus have been evaluated.
The Kingdom of Bahrain is a group of small islands located at Arabian Gulf with an approximate population of 650,000. A primary health care organization with a network of 20 health centers across the country provides health care including dispensing essential drugs. Each of these health centers is equipped with laboratory facilities for routine investigations and a theater for minor surgical procedures. The number of primary care physicians in each health center varies between 4 and 11. Any patient requiring special investigations and consultation with specialists or admission is referred to Salmaniya Medical Centre (SMC) where secondary - tertiary care is provided.
Subjects and investigations
Diabetic hypertensive patients (initially identified based on the information gathered from laboratory investigation requests by primary care physicians and verified thereafter by medical records) were included. Laboratory investigation requests from primary care physicians for patients having chronic diseases such as hypertension and type 2 diabetes mellitus, those requiring routine blood chemistry assessment (fasting glucose, total cholesterol, creatinine, and potassium), and other optional investigations [low-density lipoprotein (LDL) cholesterol, triglycerides, uric acid and plasma renin activity, plasma aldosterone, and urinary catecholamines]  are routinely analyzed in SMC biochemistry laboratory.
The laboratory investigation requests for those with a diagnostic label of hypertension and type 2 diabetes were obtained between January 2001 and February 2001 from the biochemistry laboratory at SMC. Laboratory investigation reports were retrieved through the SMC database. These reports also included information about patients' age, gender and medical records number at the health centers. Medical records of eligible patients were subsequently retrieved manually at the health centers to confirm the diagnosis, to obtain BP records (during the first few follow-up visits after receipt of laboratory reports) and to obtain treatment modification or intervention (usually second or third visits over a period of 2-3 months thereafter), and to obtain information on drugs or other therapeutic interventions prescribed.
A patient was labeled as diabetic hypertensive if he/she received antihypertensive and antidiabetics (oral antidiabetics and insulin) drugs concomitantly, and/or if the BP and hyperglycemia were controlled with nonpharmacologic interventions. Therapeutic target BP, fasting blood glucose (FBG), and glycated hemoglobin (HbA 1C ) were <130/<85 mm Hg, <6.1 mmol/l, and <7%, respectively. Overweight was defined as a body mass index (BMI) ≥25 - <30 kg/m 2 , and obesity as a BMI ≥ 30 kg/m 2 . Dyslipidemia was considered when the serum cholesterol concentration was >5.2 mmol/l, or the serum triglycerides concentration was >1.8 mmol/l or both, and if the patient was receiving lipid-lowering drugs. Subjects with a history of MI, angina pectoris, and coronary artery bypass surgery were pooled as a subgroup of ischemic heart diseases. Hyperuricemia was defined as serum uric acid >350 µmol/l for women and >440 µmol/l for men. Complementary (rational) antihypertensive combination therapy is defined as a combination of two or more antihypertensives with complementary mechanisms of action that are additive to provide optimal BP control. 
Antihypertensive drugs available at health centers at the time of data collection were: angiotensin converting enzyme inhibitors (ACEIs) (captopril, lisinopril, enalapril, perindopril); b-blockers (atenolol, propranolol); calcium channel blockers (CCBs, immediate- and sustained-release nifedipine, immediate-release diltiazem and verapamil); diuretics (hydrochlorothiazide [HCTZ], HCTZ and triamterene fixed-dose combination, chlorthalidone, sustained-release indapamide); methyldopa, hydralazine and reserpine/dihydroergocristine/clopamide (fixed-dose) combination. Among antidiabetic drugs, biguanide (metformin), second-generation sulfonylureas (glibenclamide, gliclazide, glipizide), and various preparations of short (regular)- and intermediate-acting insulins were available.
Data were analyzed using Statistical Package for the Social Science (SPSS/PC+, Version 9.0). χ2 -test without Yate's correction was used to test the difference between proportions and two-tailed t -test for continuous variables. The 95% confidence intervals were calculated with Wald's method. A P -value < 0.05 was considered statistically significant.
Permission to carry out the study was obtained from the Assistant Undersecretary for Primary Care, Ministry of Health, Bahrain. Confidentiality of both patient- and physician-related information was ensured.
Of 417 diabetic hypertensive patients 392 were included in this study, whereas, 25 (6%) were excluded because their medical records were nonretrievable. Among these 392 patients, 127 (32.4%) were men (mean age in years ± SD: 58.3 ± 10.5; median 61.0; range 29-79), whereas 265 (67.6%) were women (mean age 56.1 ± 10.9; median 56.0; range 35-89). The mean bodyweight (kg) was 81.0 ± 18.1 ( n = 78) for men, and 80.1 ± 18.5 ( n = 142) for women. The mean height (cm) for male and female patients was 168.3 ± 7.8 ( n = 78) and 155.0 ± 7.2 ( n = 142), respectively ( P < 0.001). Women had significantly greater mean BMI than men [33.3 ± 6.8 kg/m 2 ( n = 142) vs. 28.6 ± 5.3 kg/m 2 ( n = 78); P < 0.0001]. Women also had significantly greater waist circumference than men [108.4 ± 14.4 cm ( n = 90) vs. 101.6 ± 13.9 cm ( n = 45); P = 0.009]. No significant difference in mean waist-hip ratio for men and women was observed [0.99 ± 0.04 ( n = 44) vs. 0.99 ± 0.06 ( n = 90)].
Blood pressure and laboratory parameters of diabetic hypertensive men and women are presented in [Table 1]. The BP target <130/<85 mm Hg was achieved in 8.7% ( n = 11/127) men and 8.3% ( n = 22/265) women ( P = 0.99). The target HbA 1C concentration <7% was attained in 14.1% ( n = 11/78) of men and in 12.2% ( n = 18/147) of women ( P = 0.18). There were no gender differences in proportions of patients achieving the recommended BP and HbA 1C targets.
The most common antihypertensive drug class prescribed was ACEIs (54%); male patients were more often treated with ACEIs than female patients (63.7% vs. 49.4%; P = 0.006) [Table 2]. Approximately two-third of patients were on antihypertensive monotherapy (60.2%) (men 63% vs. women 58.9%, P = 0.43). No significant differences in prescribing pattern were observed between men and women with diabetic hypertension treated with either monotherapy or with antihypertensive combination therapies [Figure 1].
The overall proportion of noncomplementary two-drug antihypertensive combinations prescribed was 31.1% (men 41.1 vs. women 27.2; P = 0.13). ACEI/ β-blocker noncomplementary two-drug combination was 25.4%, prescribed to male patients in a rate significantly higher than in females ( P = 0.04; [Table 3]). Other noncomplementary two-drug regimens included combinations of methyldopa with either an ACEI (2.5%) or a diuretic (1.7%) or a β-blocker (0.8%), and a combination of losartan plus moduretic (a fixed dose HCTZ with amiloride) (0.8%). The overall proportion of noncomplementary three-drug antihypertensive combinations was 82.2% (men 72.8% vs. women 88.2%; P = 0.29). ACEI/β-blocker/diuretic-based regimen was the most common three-drug combination (42.9%) prescribed. The proportion of other noncomplementary three-drug regimens were as follows: ACEI/β-blocker/CCB (24.9%), ACEI/CCB/methyldopa (3.6%), ACEI/diuretic/methyldopa (3.6%), β-blocker/CCB/methyldopa (3.6%) and β-blocker/diuretic/ methyldopa (3.6%).
The overall prescription of oral antidiabetic agents and insulin according to gender is shown in [Table 2]. Glibenclamide was the most frequently prescribed drug in both genders (men 50.4% vs. women 52.1). Females were more often treated with insulin than male patients (12.5% vs. 6.3%; P = 0.04); no other significant differences with respect to drug selection [Table 2], and rank-order of prescribed antidiabetics, either as monotherapy or as combinations, were observed [Figure 1].
Approximately 13% of diabetic hypertensive patients were on lipid-lowering drugs; no gender difference was observed [Table 2]. The overall prescribing of antithrombotic aspirin was 11.5%; men were more often treated with aspirin than women (21.3% vs. 6.8%; P < 0.0001). The proportion of cardiovascular risk factors notably overweight, obesity, hypercholesterolemia, and hyperuricemia were significantly greater in women compared to men [Table 4]. Ischemic heart disease was more prevalent among male patients ( P = 0.02).
This prescription audit study revealed that in diabetic hypertensives a BP target ≤130/85 mm Hg was achieved only in 8.4% of patients treated at primary care setting in Bahrain. This rate of BP control was markedly lower than that reported in USA,  Saudi Arabia,  and in France  using BP < 130/80 mm Hg threshold; Sweden  using BP < 140/80 mm Hg; in Bangladesh and India  and more recently 19.7% in USA  using BP target < 130/85 mm Hg, a target comparable to that used in our study. We also found a lack of gender-based difference in the proportion of patients who achieved the recommended goal BP, a finding that corroborates  and differs  from other studies. Poor rate of BP control in our study may be partly due to: (a) prescribing of antihypertensive monotherapy to majority of patients [Figure 1], whereas combination of antihypertensives are often needed to achieve the recommended BP targets in diabetic hypertensive patients ,,,, ; approximately 10% of patients were on three or more drug combination therapy [Figure 1]; (b) prescribing noncomplementary two-drug combinations ,,, (31.2%) and three-drug combinations  (82.2%) [Table 3]; (c) most patients had metabolic syndrome, which increases the cardiovascular risk and renders the BP target difficult to achieve  ; (d) high prevalence of overweight - obesity in male (75.6%) and female (91.5%) patients [Table 4]; obesity is associated with elevated BP, diminished antihypertensive drug efficacy, and increased cardiovascular risk. ,
ACEIs were the most often prescribed antihypertensive drugs in our study, a profile comparable to findings of other studies. ,,,, ACEIs have favorable impact on cardiovascular and renal outcomes. ,,,, Men were more often prescribed ACEIs than women ( P < 0.05). The explanation for this prescribing pattern may be related to: (a) awareness of many primary care physicians about a lack of adverse effect of ACEIs on sexual function in men  ; and (b) higher incidence of ACEI-induced cough in women than in men. 
Comorbidity with diabetes and hypertension appears to be a risk factor, contributing independently to sexual dysfunction in men.  Sexual dysfunction has been often associated with the use of thiazide diuretics, b-blockers, and centrally acting adrenergic inhibitors.  Atenolol, the second ranked antihypertensive was prescribed in both genders (37.7% in male and 44.8% in female) at a daily dose of 100 mg. In addition to potential iatrogenic erectile dysfunction in male, , β-blockers in high doses mask the symptoms of hypoglycemia, ,, and can result in adverse metabolic effects.
A reluctance of many physicians to prescribe diuretics was noted [Table 2], although low-dose diuretics are effective in patients with diabetic hypertension, and are associated with minimal dose-related sexual dysfunction  and adverse metabolic effects.  Low-dose diuretic, unless contraindicated, should be included as an essential component of combination therapy in hypertensives.  Low dose of thiazide in combination with potassium sparing diuretics, ACEIs, ARBs, β-blockers, and CCBs have been proven to be rational combinations. ,,, The use of diuretics in diabetic hypertensive patients has been reported to protect against coronary disease to an even greater degree than in nondiabetic hypertensives.  Appropriate low doses of diuretics and b-blockers, therefore, should be considered , since 27.8% of male patients reported sexual problems in our study (data not shown).
Gender-based differences in antihypertensive drug use in general practice have been reported earlier.  Physician characteristics such as a lack of residency training in family medicine, and nonevidence-based attitude that men have greater absolute risk of coronary heart diseases than women, and higher prevalence of ankle edema among women were considered explanations for the choice of β-blockers in men and diuretics for hypertensive women. 
Further more, among older women with no history of cardiovascular diseases (CVD), other than hypertension, a drug regimen comprising CCB/diuretics was associated with greater risk of CVD mortality versus β-blocker/diuretics. Risks were similar for ACEI/diuretics and β-blockers/diuretics.  Monotherapy with diuretics was equal or superior to other monotherapies in preventing CVD complications of high BP in older women. 
As regards glycemic control, fewer than 13% (14.1% men; 12.2% women; P = 0.18) of patients (in whom HbA 1C data were available) achieved the target HbA 1C <7% in our study sample. This proportion was lower than that reported in USA.  Poor glycemic control in our study, at least in part, can be due to less intensive drug therapy. This view is supported by the finding that single drug therapy was prescribed for approximately 50% of male and female diabetic patients with hypertension [Figure 1]. In the United Kingdom Prospective Diabetics Study, only about 25% of patients treated with monotherapy achieved target HbA 1C <7% of whom 42% were on insulin.  At least 40% of patients with type 2 diabetes eventually required insulin to maintain adequate glycemic control.  Of 392 patients in our study, 41 (10.5%) were treated with insulin either alone or in combination with oral antidiabetics; 18 (4.6%) were on insulin alone, 20 (5.1%) were on two-drug combinations and 3 (0.8%) were on three-drug combinations (data not shown). The association between obesity in diabetic hypertensive females and poor glycemic control in our study partly explains why female patients received insulin at a rate significantly greater than males. A conservative use of insulin may be because: (a) some physicians erroneously view insulin to be the last resort therapy; and (b) a reluctance of others due to concerns about bodyweight gain and hypoglycemic risk.  Patient-related barriers to insulin therapy appear to play a minimal role since only 2.3% patients refused insulin therapy.
Metformin was relatively underutilized although the majority of patients in both genders were overweight or obese [Table 4]. Metformin is as effective as sulfonylurea in lowering HbA 1C concentration and results in moderate weight loss  ; diarrhea  may be the main reason for its underutilization. Newer oral antidiabetics with proven efficacy and safety should be included in the primary care essential drug list to expand the therapeutic options for maintaining target glycemic control.
Lipid-lowering drugs were underutilized although these drugs decrease the rate of coronary events in diabetic than nondiabetic subjects,  and need to be prescribed to all subjects with diabetes as if they had prior coronary heart disease. ,, A lack of gender-based difference was observed with regard to lipid-lowering drugs although: (a) mean total cholesterol was significantly greater in female patients [Table 1]; (b) LDL cholesterol for both genders was > 3.35 mmol/l (the cutoff level recommended for pharmacologic intervention);  and (c) the proportion of females with total cholesterol ≥5.2 mmol/l was significantly greater than in male. Although the lipid profile of our study population justifies intervention with statins, fibrates were used instead in about two-third of patients [Table 2], because statins were restricted for referral patients at the time of data collection.
Low-dose aspirin is considered as a primary prevention strategy in high-risk diabetic subjects  to reduce adverse clinical outcomes, especially major cardiovascular events. , Contrary to the expectation, antithrombotic strategy has received little attention since aspirin was prescribed conservatively. Men were more likely to be on aspirin ( P < 0.0001; [Table 2]) because ischemic heart disease was more prevalent in men ( P = 0.02; [Table 4]).
Our study has confirmed that women with diabetes were less aggressively treated for many modifiable CVD risk factors than men with diabetes. Similar findings have been reported previously. ,,, An aggressive treatment of CVD risk factors in this population offers specific targets for improving diabetes care. The low rates of multiple risk factor control in patients with diabetes also highlight the challenges for attaining/achieving evidence-based goals in primary care. It would be interesting to determine the impact of more recent guidelines on BP and glycemic control rates and risk factor control.  In addition, differences in coping strategies in men and women with diabetes  also need to be further explored.
Limitation of study
Drug compliance, which is a major problem in patients with chronic diseases, has not been considered in this descriptive study. Gender as a determinant of BP and glycemic control from a developing country-perspective needs a further evaluation. The generalizability of our findings needs to be carefully considered within the framework of organization of the health care system of a country.
In both men and women, BP and glycemia were inadequately controlled in diabetic hypertensive patients treated by primary care physicians. Prescribing of ACEIs and aspirin in favor of males, and insulin in favor of females, were the only observed gender-based differences in drug therapy. Cardiovascular preventive strategies have received little attention regardless of gender. Updating the primary care-essential drug list to provide more efficacious and complementary therapies for optimal BP and glycemic control is needed. Continuing professional education addressing pharmacotherapy should be encouraged. Effective prevention strategies to reduce CVD mortality and disability in developing countries are required. Gender-based treatment inequities also need to be addressed.
[Table 1], [Table 2], [Table 3], [Table 4]