Background Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response.
Background
Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response.Methods Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline.
Methods
Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6–3.9 mM/l and HDL cholesterol ≤ 1.05 mM/l for women and ≤ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline.Results After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m 2 ) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate.
Results
After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m 2 ) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs -10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate.Conclusions Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated.
Conclusions
Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated.

Background Hypertriglyceridemia in combination with abnormally low concentrations of HDL cholesterol (High Density Lipoprotein Cholesterol) is one of the most common and atherogenic profiles of lipid metabolism [ 1 ]. In the PROCAM study [ 2 ], the 6-year incidence of coronary events in men aged between 40 and 60 years, was twelve times higher than in the control group. The prevalence of this abnormality varies among ethnic groups [ 3 ]. It is found in 13% of the Mexican adults living in urban areas [ 4 ]. It is more common in men than in women (20.9% vs 7.2%) and in some age groups (i.e. men aged 30 to 39 years) this prevalence is as high as 30%. This lipid profile is the most frequent form of dyslipidemia in the metabolic syndrome [ 5 ]. However it is also found in subjects affected by primary dyslipidemias (e.g familial combined hyperlipidemia). In the Veteran Affairs HDL Intervention Trial (VAHIT), the use of a fibrate (gemfibrozil) resulted in a 22% reduction in the incidence of cardiovascular events in subjects with low HDL cholesterol and a broad range of triglyceride values [ 6 ]. The benefit was accounted for by the positive effects obtained in cases with insulin resistance [ 7 ]. In spite of these positive results, there are few studies assessing the efficacy of other fibrates in the treatment of this form of dyslipidemia [ 8 ]. Relevant data such as the percentage of cases that achieve treatment goals are not described in the majority of these reports. Also, variables predicting a greater likelihood of achieving treatment goals remain to be identified. Our objective was to assess the efficacy and safety of ciprofibrate (100 mg/day) for the treatment of cases with hypertriglyceridemia / hypoalphalipoproteinemia in an open label, multicenter, international study. A clinically oriented approach is used for the description of the results.
Background
Hypertriglyceridemia in combination with abnormally low concentrations of HDL cholesterol (High Density Lipoprotein Cholesterol) is one of the most common and atherogenic profiles of lipid metabolism [ 1 ]. In the PROCAM study [ 2 ], the 6-year incidence of coronary events in men aged between 40 and 60 years, was twelve times higher than in the control group. The prevalence of this abnormality varies among ethnic groups [ 3 ]. It is found in 13% of the Mexican adults living in urban areas [ 4 ]. It is more common in men than in women (20.9% vs 7.2%) and in some age groups (i.e. men aged 30 to 39 years) this prevalence is as high as 30%. This lipid profile is the most frequent form of dyslipidemia in the metabolic syndrome [ 5 ]. However it is also found in subjects affected by primary dyslipidemias (e.g familial combined hyperlipidemia).In the Veteran Affairs HDL Intervention Trial (VAHIT), the use of a fibrate (gemfibrozil) resulted in a 22% reduction in the incidence of cardiovascular events in subjects with low HDL cholesterol and a broad range of triglyceride values [ 6 ]. The benefit was accounted for by the positive effects obtained in cases with insulin resistance [ 7 ]. In spite of these positive results, there are few studies assessing the efficacy of other fibrates in the treatment of this form of dyslipidemia [ 8 ]. Relevant data such as the percentage of cases that achieve treatment goals are not described in the majority of these reports. Also, variables predicting a greater likelihood of achieving treatment goals remain to be identified. Our objective was to assess the efficacy and safety of ciprofibrate (100 mg/day) for the treatment of cases with hypertriglyceridemia / hypoalphalipoproteinemia in an open label, multicenter, international study. A clinically oriented approach is used for the description of the results.Materials and Methods The trial included men and post-menopausal or non-pregnant women aged between 30 and 70 years who had hypertriglyceridemia (fasting concentrations between 1.68–3.9 mM/l (150 – 350 mg/dl) and hypoalphalipoproteinemia (HDL cholesterol ≤ 1.05 mM/l (40 mg/dl) for women and ≤ 0.92 mM/l (35 mg/dl) for men). The LDL cholesterol had to be lower than 4.2 mM/l (160 mg/dl). Patients were excluded if they had an acute coronary event during the three months preceding the study, type 1 diabetes, uncontrolled hypertension, severe renal dysfunction, nephrotic syndrome or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 1.5 × the upper limit of normal (ULN), or if their creatine phosphokinase (CPK) levels were > 3 × ULN. Consumption of any lipid-altering drug within the previous 4 weeks (6 months for probucol) prevented entry into the study. Patients could be receiving other concomitant medication as long as the dosage was not modified during the study. The Ethics Committee in each institution approved the protocol and every patient provided witnessed, written informed consent prior to entering the study. This was a multicenter, international, open-label study. Patients were recruited from 25 lipid clinics from México (n = 152), Brazil (n = 129), Chile (n = 78) and Colombia (n = 78). Cases fulfilling the inclusion criteria were invited to participate. The initial visit included a medical evaluation, a physical examination and the prescription of an isocaloric diet consisting of 50% carbohydrate, 30% fat, 20% protein with a cholesterol content of 200 mg [ 9 ]. Blood samples were obtained after a 9–12 h fasting period. All patients were assigned to receive ciprofibrate 100 mg at bedtime. The second and final visit was scheduled 4 months later. During this visit drug compliance and safety profile were assessed and body weight as well as laboratory parameters were measured. Drug compliance was measured by counting the returned pills. Adherence to the diet was not assessed during the study The primary efficacy parameter was the percentage change in triglycerides from baseline. Secondary efficacy parameters included the percentage change in total cholesterol, HDL cholesterol and non-HDL cholesterol from baseline. Non-HDL cholesterol was calculated by subtracting the HDL cholesterol from the total cholesterol levels. In a post hoc analysis, the percentage of cases that achieved the treatment goals proposed by the ATP-III recommendations [ 10 ] on the final visit was also estimated. At each visit, AST, ALT, fasting plasma glucose and CPK levels were measured. Clinically relevant complications were defined as either CPK > 5 × ULN accompanied by muscle pain, tenderness or weakness or ALT or AST > 3 × ULN. Patients were excluded from the study if they developed severe hyperglycemia or any other significant complication to treatment. Other reasons for premature withdrawal were lack of compliance to the medication. Cases were instructed to contact their physician in case of any side effect. All samples were analyzed in a central laboratory (Quest laboratories). In Brazil, the local laboratory of every center was used instead. Blood samples were taken after an overnight fast (≥ 9 hours). Measurements were performed during the first 24 hours after the blood was drawn; blood samples were kept at 4°C until the analysis. All laboratory analyses were performed with commercially available standardized methods. Glucose was measured using the glucose oxidase method. Total serum cholesterol and triglycerides levels were measured using an enzymatic method. HDL cholesterol levels were assessed using phosphotungstic acid and Mg2+. Statistical analysis was performed using SPSS for Windows version 10. An intention to treat analysis was used. Two sided ANOVA tests were used for assessing differences between groups for continuous variables. All categorical variables were analyzed using the chi squared test. Multiple logistic regression models were constructed for the identification of variables associated with the achievement of treatment goals.
Materials and Methods
The trial included men and post-menopausal or non-pregnant women aged between 30 and 70 years who had hypertriglyceridemia (fasting concentrations between 1.68–3.9 mM/l (150 – 350 mg/dl) and hypoalphalipoproteinemia (HDL cholesterol ≤ 1.05 mM/l (40 mg/dl) for women and ≤ 0.92 mM/l (35 mg/dl) for men). The LDL cholesterol had to be lower than 4.2 mM/l (160 mg/dl). Patients were excluded if they had an acute coronary event during the three months preceding the study, type 1 diabetes, uncontrolled hypertension, severe renal dysfunction, nephrotic syndrome or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels > 1.5 × the upper limit of normal (ULN), or if their creatine phosphokinase (CPK) levels were > 3 × ULN. Consumption of any lipid-altering drug within the previous 4 weeks (6 months for probucol) prevented entry into the study. Patients could be receiving other concomitant medication as long as the dosage was not modified during the study.The Ethics Committee in each institution approved the protocol and every patient provided witnessed, written informed consent prior to entering the study.This was a multicenter, international, open-label study. Patients were recruited from 25 lipid clinics from México (n = 152), Brazil (n = 129), Chile (n = 78) and Colombia (n = 78). Cases fulfilling the inclusion criteria were invited to participate. The initial visit included a medical evaluation, a physical examination and the prescription of an isocaloric diet consisting of 50% carbohydrate, 30% fat, 20% protein with a cholesterol content of 200 mg [ 9 ]. Blood samples were obtained after a 9–12 h fasting period. All patients were assigned to receive ciprofibrate 100 mg at bedtime. The second and final visit was scheduled 4 months later. During this visit drug compliance and safety profile were assessed and body weight as well as laboratory parameters were measured. Drug compliance was measured by counting the returned pills. Adherence to the diet was not assessed during the studyThe primary efficacy parameter was the percentage change in triglycerides from baseline. Secondary efficacy parameters included the percentage change in total cholesterol, HDL cholesterol and non-HDL cholesterol from baseline. Non-HDL cholesterol was calculated by subtracting the HDL cholesterol from the total cholesterol levels. In a post hoc analysis, the percentage of cases that achieved the treatment goals proposed by the ATP-III recommendations [ 10 ] on the final visit was also estimated.At each visit, AST, ALT, fasting plasma glucose and CPK levels were measured. Clinically relevant complications were defined as either CPK > 5 × ULN accompanied by muscle pain, tenderness or weakness or ALT or AST > 3 × ULN. Patients were excluded from the study if they developed severe hyperglycemia or any other significant complication to treatment. Other reasons for premature withdrawal were lack of compliance to the medication. Cases were instructed to contact their physician in case of any side effect.All samples were analyzed in a central laboratory (Quest laboratories). In Brazil, the local laboratory of every center was used instead. Blood samples were taken after an overnight fast (≥ 9 hours). Measurements were performed during the first 24 hours after the blood was drawn; blood samples were kept at 4°C until the analysis. All laboratory analyses were performed with commercially available standardized methods. Glucose was measured using the glucose oxidase method. Total serum cholesterol and triglycerides levels were measured using an enzymatic method. HDL cholesterol levels were assessed using phosphotungstic acid and Mg2+.Statistical analysis was performed using SPSS for Windows version 10. An intention to treat analysis was used. Two sided ANOVA tests were used for assessing differences between groups for continuous variables. All categorical variables were analyzed using the chi squared test. Multiple logistic regression models were constructed for the identification of variables associated with the achievement of treatment goals.Results Four hundred thirty seven patients were included. The clinical characteristics of the study subjects are shown in table  1 . Almost half of the population had a body mass index between 25 and 30 kg/m 2  (n = 221); an additional 32.5% were obese (n = 142) Diabetes was present in 125 subjects (28.7%). Table 1 Baseline characteristics of the patients included in study (n = 437) Variable N = 437 Sex  Male (n(%)) 239 (54.7)  Female (n(%)) 198 (45.3) Age (years)* 54.7 ± 12.1 Body mass index (kg/m 2 ) 28.8 ± 4.6 Diabetes (n(%)) 125 (28.7) Fasting plasma glucose (mM/l)* 5.2 ± 0.6 Family history of dyslipidemia (n(%)) 171 (39.2) Coronary heart disease (n(%)) 196 (45) Aspartate aminotranferase (mU/l) 23 ± 11 Alanine aminotransferase (mU/l) 26 ± 14 Data expressed as mean ± standard deviation. *To convert to mg/dl, multiply by 18 Both evaluations were completed in every case. The medication was stopped before the trial was completed by 117 subjects (26.7%). In the majority of cases this was not related to side effects (see below). In addition, 46 cases (10.5%) had poor compliance to the medication. The body weight remained constant in all patients. The alcohol and tobacco consumption was not modified during the study. Ciprofibrate treatment and diet had a significant beneficial effect on the lipid profile, as shown in table  2 . After 4 months of treatment, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10.1% (p < 0.001). Non-HDL cholesterol was decreased by 19.2% (p < 0.001). Total cholesterol was also favorably modified (-14.9%, p < 0.001). In contrast, LDL cholesterol had a minor modification (-5.4%, p < 0.001). A significant decrease in fasting glycemia was observed in both obese and diabetic cases. This change was not found in lean subjects. Table 2 Changes in the lipid profile and clinical characteristics between baseline and post-treatment values Intention to treat analysis N = 437 Baseline Final Percent change Triglycerides (mM/l)  † 3.01 ± 0.7 1.61 ± 0.8 -44 ± 33* HDL Cholesterol (mM/l) ‡ 0.91 ± 0.1 0.98 ± 0.4 10 ± 52* Non-HDL cholesterol (mM/l) ‡ 4.57 ± 0.9 3.61 ± 1.5 -19 ± 36* Cholesterol (mM/l) ‡ 5.5 ± 0.9 4.57 ± 1.8 -14.9 ± 35* LDL Cholesterol (mM/l) ‡ 3.1 ± 0.9 2.8 ± 1.3 -5.4 ± 59* Mean ± standard deviation are presented. *p < 0.001  † To convert to mg/dl multiple by 89  ‡ To convert to mg/dl multiple by 38 The achievement of treatment goals is the ultimate aim of lipid-lowering therapy. Almost half of the cases had reduced their triglyceride concentrations below 1.68 mM/l (150 mg/dl) (n= 191(43.7%). HDL cholesterol levels above 1.05 mM/l (40 mg/dl) were found in 51% of the cases (n = 223). Also, a significant proportion of the subjects (63.15%, n = 276) achieved the non-HDL cholesterol goal 4.2 mM/l (< 160 mg/dl). The LDL cholesterol goal < 3.4 mM/l (< 130 mg/dl) was attained by 56.2 % (n = 246). A full correction of the hypertrigliceridemia / low HDL cholesterol occurred in 129 subjects (29.5%). Many of them also had a non-HDL cholesterol level below 4.2 mM/l (160 mg/dl) (n = 101, 23.1%) The lipid response during treatment differed between cases with a body mass index above or below 25 kg/m 2 . As is shown in figure  1 , the percentage change in HDL cholesterol was higher in lean subjects. In contrast, the non-HDL cholesterol concentration had a significantly greater reduction among subjects with excess body weight. Both differences remained significant even after adjusting for age and gender. The lipid profile did not differ between these groups during the initial visit. Figure 1 The percentage of change in the lipid parameters is different in cases with a body mass index above 25 kg/m 2  compared to the response observed in lean individuals during treatment with ciprofibrate and diet. Patients with diabetes had moderate hyperglycemia during the study. Their fasting glycemia was 7.7 ± 2.6 mM/l (139 ± 47 mg/dl) at baseline. A small but statistically significant decrease in glucose concentration was observed at the end of the trial (5.7 ± 3 mM/l, 104 ± 54 mg/dl p < 0.001). At baseline, their lipid profile differed, from the non-diabetic subjects, only with regards to higher triglyceride concentrations (3.13 ± 0.97 vs 2.95 ± 0.66 mM/l, p < 0.001). The lipid response to ciprofibrate and dietary treatment did not differ from that observed in the whole group. Individuals with a family history of dyslipidemia (n = 171) had higher cholesterol, triglycerides and LDL cholesterol at baseline compared to the rest of the population. The lipid response to treatment was similar to that reported in the whole group. Multiple regression models were constructed to identify variables associated with the achievement of the treatment goals. For every target value, the main determinants were the baseline value and the percentage change after treatment. No other parameter provided additional information in any of the models. Thus, we analyzed the variables associated with the percentage change during treatment. The non-HDL cholesterol model provided more information compared to models derived from the other lipid parameters. In the non-HDL cholesterol model, a body mass index greater than 25 kg/m 2 , the triglyceride response and the coexistence of cholesterol above 5.2 mM/l (200 mg/dl) (mixed hyperlipidemia) were predictors for a greater non-HDL cholesterol response (table  3 ). For both, the HDL cholesterol and the triglycerides models, the inclusion of a body mass index < 25 kg/m 2  added little information and had only borderline statistical significance. No other clinically relevant variable was associated with the percentage change of any other lipid parameter. Table 3 Multiple regression model using as dependent variable percent of change in non-HDL cholesterol concentration Variable Beta coefficient ± standard error p value Constant 14.4 ± 2.6 < 0.001 BMI < 25 kg/m 2 7.6 ± 3.6 0.036 Mixed hyperlipidemia 0.82 ± 0.2 0.003 Percent of change of triglycerides 0.68 ± 0.4 < 0.001 Correlation coefficient = 0.647, r 2  = 0.419, p = 0.001 BMI, Body mass index Liver function tests were not modified by the treatment. No patient had a significant alteration of any of the laboratory tests. There were no incidents of either myopathy or liver dysfunction. No persistent elevations in ALT, AST or CPK, defined as clinically relevant, were reported during the course of the study.
Results
Four hundred thirty seven patients were included. The clinical characteristics of the study subjects are shown in table  1 . Almost half of the population had a body mass index between 25 and 30 kg/m 2  (n = 221); an additional 32.5% were obese (n = 142) Diabetes was present in 125 subjects (28.7%).Baseline characteristics of the patients included in study (n = 437)VariableN = 437Data expressed as mean ± standard deviation. *To convert to mg/dl, multiply by 18Both evaluations were completed in every case. The medication was stopped before the trial was completed by 117 subjects (26.7%). In the majority of cases this was not related to side effects (see below). In addition, 46 cases (10.5%) had poor compliance to the medication. The body weight remained constant in all patients. The alcohol and tobacco consumption was not modified during the study.Ciprofibrate treatment and diet had a significant beneficial effect on the lipid profile, as shown in table  2 . After 4 months of treatment, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10.1% (p < 0.001). Non-HDL cholesterol was decreased by 19.2% (p < 0.001). Total cholesterol was also favorably modified (-14.9%, p < 0.001). In contrast, LDL cholesterol had a minor modification (-5.4%, p < 0.001). A significant decrease in fasting glycemia was observed in both obese and diabetic cases. This change was not found in lean subjects.Changes in the lipid profile and clinical characteristics between baseline and post-treatment valuesIntention to treat analysis N = 437BaselineFinalPercent changeMean ± standard deviation are presented. *p < 0.001  † To convert to mg/dl multiple by 89  ‡ To convert to mg/dl multiple by 38The achievement of treatment goals is the ultimate aim of lipid-lowering therapy. Almost half of the cases had reduced their triglyceride concentrations below 1.68 mM/l (150 mg/dl) (n= 191(43.7%). HDL cholesterol levels above 1.05 mM/l (40 mg/dl) were found in 51% of the cases (n = 223). Also, a significant proportion of the subjects (63.15%, n = 276) achieved the non-HDL cholesterol goal 4.2 mM/l (< 160 mg/dl). The LDL cholesterol goal < 3.4 mM/l (< 130 mg/dl) was attained by 56.2 % (n = 246). A full correction of the hypertrigliceridemia / low HDL cholesterol occurred in 129 subjects (29.5%). Many of them also had a non-HDL cholesterol level below 4.2 mM/l (160 mg/dl) (n = 101, 23.1%)The lipid response during treatment differed between cases with a body mass index above or below 25 kg/m 2 . As is shown in figure  1 , the percentage change in HDL cholesterol was higher in lean subjects. In contrast, the non-HDL cholesterol concentration had a significantly greater reduction among subjects with excess body weight. Both differences remained significant even after adjusting for age and gender. The lipid profile did not differ between these groups during the initial visit.Patients with diabetes had moderate hyperglycemia during the study. Their fasting glycemia was 7.7 ± 2.6 mM/l (139 ± 47 mg/dl) at baseline. A small but statistically significant decrease in glucose concentration was observed at the end of the trial (5.7 ± 3 mM/l, 104 ± 54 mg/dl p < 0.001). At baseline, their lipid profile differed, from the non-diabetic subjects, only with regards to higher triglyceride concentrations (3.13 ± 0.97 vs 2.95 ± 0.66 mM/l, p < 0.001). The lipid response to ciprofibrate and dietary treatment did not differ from that observed in the whole group. Individuals with a family history of dyslipidemia (n = 171) had higher cholesterol, triglycerides and LDL cholesterol at baseline compared to the rest of the population. The lipid response to treatment was similar to that reported in the whole group.Multiple regression models were constructed to identify variables associated with the achievement of the treatment goals. For every target value, the main determinants were the baseline value and the percentage change after treatment. No other parameter provided additional information in any of the models. Thus, we analyzed the variables associated with the percentage change during treatment. The non-HDL cholesterol model provided more information compared to models derived from the other lipid parameters. In the non-HDL cholesterol model, a body mass index greater than 25 kg/m 2 , the triglyceride response and the coexistence of cholesterol above 5.2 mM/l (200 mg/dl) (mixed hyperlipidemia) were predictors for a greater non-HDL cholesterol response (table  3 ). For both, the HDL cholesterol and the triglycerides models, the inclusion of a body mass index < 25 kg/m 2  added little information and had only borderline statistical significance. No other clinically relevant variable was associated with the percentage change of any other lipid parameter.Multiple regression model using as dependent variable percent of change in non-HDL cholesterol concentrationVariableBeta coefficient ± standard errorp valueCorrelation coefficient = 0.647, r 2  = 0.419, p = 0.001 BMI, Body mass indexLiver function tests were not modified by the treatment. No patient had a significant alteration of any of the laboratory tests. There were no incidents of either myopathy or liver dysfunction. No persistent elevations in ALT, AST or CPK, defined as clinically relevant, were reported during the course of the study.Discussion The combination of hypertriglyceridemia / low HDL cholesterol is a common abnormality of lipoprotein metabolism and is associated with increased cardiovascular risk. Our data show that ciprofibrate and an isocaloric diet are an effective treatment for this dyslipidemia. However, there was significant variation in response to treatment between individuals. Excess body weight may be an important determinant of the lipid response. It is associated with a greater degree of non-HDL cholesterol reduction and a relatively smaller elevation in HDL cholesterol. A significant improvement in plasma triglycerides and HDL cholesterol concentrations resulted from the administration of ciprofibrate and dietary modifications. Our results are in agreement with previous studies [ 11 - 15 ]. This study differs from previous reports due to its design. We wanted to assess the lipid response to ciprofibrate in a real life environment. Hence, the highly controlled conditions of a randomized, double blind study were avoided. Also, we limited our inclusion criteria to subjects with hypertriglyceridemia / low HDL cholesterol, instead of including subjects with a wide variety of lipid profiles. The results are in accordance with the uncontrolled design of the study. By the use of ciprofibrate and isocaloric diet, almost half of the cases achieved the triglyceride goal (1.68 mM/l, 150 mg/dl). HDL cholesterol levels above 40 mg/dl were found in 51% of the cases. The full correction of the combination of hypertriglyceridemia / low HDL cholesterol occurred in a third of the population. This rate is similar to that reported for the LDL cholesterol goals achieved by the use of statins. Thus, our results reflect the strengths and limitations of treating this lipid abnormality in an uncontrolled setting. A large range of lipid responses was observed between individuals. There are few reports designed to analyse the determinants of the lipid response to fibrates. Robins reported a lower HDL cholesterol elevation with a fibrate when insulin resistance is present [ 7 ]. In this report, a lower HDL cholesterol response was observed in patients with excess body weight (body mass index above 25 kg/m 2 ) in comparison to that found in lean individuals. Since excess body weight is strongly associated with insulin resistance [ 16 , 17 ], our observations may be in agreement with the findings of Robins. Interestingly, the presence of insulin resistance was associated with the lowest incidence of coronary events in the VAHIT study. In our report, obese individual had a larger decrease in non-HDL cholesterol levels. The greater response in non-HDL cholesterol observed in our obese (and possibly insulin resistant) subjects may be one possible explanation for the greater benefit found in insulin resistant subjects during the VAHIT study. Our data suggest that the mechanism of action of ciprofibrate may be altered by the pathophysiology of the disorder being treated. The same phenomenon has been observed with the use of statins [ 18 , 19 ]. The greater reduction in non-HDL cholesterol in subjects with excess body weight could be explained by an increased clearance of remnants, IDL and VLDL particles. Ciprofibrate may enhance their clearance either by decreasing the concentration of the apolipoprotein CIII (an inhibitor of the lipolytic activity of the lipoprotein lipase) [ 20 - 22 ] or by increasing the mass and activity of lipoprotein lipase [ 23 ]. Genes encoding apolipoprotein CIII and lipoprotein lipase contain a PPAR-alpha response element; hence their expression may be modified during treatment with a fibrate [ 24 ]. Additional studies are needed to identify other possible determinants of the lipid response to treatment with a fibrate. Several limitations of the study must be recognized. The uncontrolled design resulted in a relatively high rate of drug discontinuation. However, this phenomenon is a common finding in studies done in open populations assessing the adherence to different lipid-lowering medications [ 25 ]. To overcome this limitation, an intention to treat analysis was used. Also, the lack of a run-in period in which the effect of diet could be measured and the absence of information about the adherence to the diet prevented us from discerning to what extent the observed result was due to fibrate alone. Finally, some of the conclusions, like the identification of the determinants of the lipid response, came from a post hoc analysis. In conclusion, ciprofibrate is effective in the treatment of patients with hypertriglyceridemia / low HDL cholesterol. Significant reductions in triglycerides and non-HDL cholesterol resulted from ciprofibrate therapy. In addition, higher HDL cholesterol levels were found at the end of the treatment. Excess body weight alters the lipid response to ciprofibrate. A greater non-HDL cholesterol lowering is achieved in subjects with excess body weight compared to that found in lean individuals. Controlled trials are needed to compare the lipid-lowering effects of ciprofibrate in groups of subjects defined by their adiposity or other markers of insulin resistance.
Discussion
The combination of hypertriglyceridemia / low HDL cholesterol is a common abnormality of lipoprotein metabolism and is associated with increased cardiovascular risk. Our data show that ciprofibrate and an isocaloric diet are an effective treatment for this dyslipidemia. However, there was significant variation in response to treatment between individuals. Excess body weight may be an important determinant of the lipid response. It is associated with a greater degree of non-HDL cholesterol reduction and a relatively smaller elevation in HDL cholesterol.A significant improvement in plasma triglycerides and HDL cholesterol concentrations resulted from the administration of ciprofibrate and dietary modifications. Our results are in agreement with previous studies [ 11 - 15 ]. This study differs from previous reports due to its design. We wanted to assess the lipid response to ciprofibrate in a real life environment. Hence, the highly controlled conditions of a randomized, double blind study were avoided. Also, we limited our inclusion criteria to subjects with hypertriglyceridemia / low HDL cholesterol, instead of including subjects with a wide variety of lipid profiles. The results are in accordance with the uncontrolled design of the study. By the use of ciprofibrate and isocaloric diet, almost half of the cases achieved the triglyceride goal (1.68 mM/l, 150 mg/dl). HDL cholesterol levels above 40 mg/dl were found in 51% of the cases. The full correction of the combination of hypertriglyceridemia / low HDL cholesterol occurred in a third of the population. This rate is similar to that reported for the LDL cholesterol goals achieved by the use of statins. Thus, our results reflect the strengths and limitations of treating this lipid abnormality in an uncontrolled setting.A large range of lipid responses was observed between individuals. There are few reports designed to analyse the determinants of the lipid response to fibrates. Robins reported a lower HDL cholesterol elevation with a fibrate when insulin resistance is present [ 7 ]. In this report, a lower HDL cholesterol response was observed in patients with excess body weight (body mass index above 25 kg/m 2 ) in comparison to that found in lean individuals. Since excess body weight is strongly associated with insulin resistance [ 16 , 17 ], our observations may be in agreement with the findings of Robins. Interestingly, the presence of insulin resistance was associated with the lowest incidence of coronary events in the VAHIT study. In our report, obese individual had a larger decrease in non-HDL cholesterol levels. The greater response in non-HDL cholesterol observed in our obese (and possibly insulin resistant) subjects may be one possible explanation for the greater benefit found in insulin resistant subjects during the VAHIT study. Our data suggest that the mechanism of action of ciprofibrate may be altered by the pathophysiology of the disorder being treated. The same phenomenon has been observed with the use of statins [ 18 , 19 ]. The greater reduction in non-HDL cholesterol in subjects with excess body weight could be explained by an increased clearance of remnants, IDL and VLDL particles. Ciprofibrate may enhance their clearance either by decreasing the concentration of the apolipoprotein CIII (an inhibitor of the lipolytic activity of the lipoprotein lipase) [ 20 - 22 ] or by increasing the mass and activity of lipoprotein lipase [ 23 ]. Genes encoding apolipoprotein CIII and lipoprotein lipase contain a PPAR-alpha response element; hence their expression may be modified during treatment with a fibrate [ 24 ]. Additional studies are needed to identify other possible determinants of the lipid response to treatment with a fibrate.Several limitations of the study must be recognized. The uncontrolled design resulted in a relatively high rate of drug discontinuation. However, this phenomenon is a common finding in studies done in open populations assessing the adherence to different lipid-lowering medications [ 25 ]. To overcome this limitation, an intention to treat analysis was used. Also, the lack of a run-in period in which the effect of diet could be measured and the absence of information about the adherence to the diet prevented us from discerning to what extent the observed result was due to fibrate alone. Finally, some of the conclusions, like the identification of the determinants of the lipid response, came from a post hoc analysis.In conclusion, ciprofibrate is effective in the treatment of patients with hypertriglyceridemia / low HDL cholesterol. Significant reductions in triglycerides and non-HDL cholesterol resulted from ciprofibrate therapy. In addition, higher HDL cholesterol levels were found at the end of the treatment. Excess body weight alters the lipid response to ciprofibrate. A greater non-HDL cholesterol lowering is achieved in subjects with excess body weight compared to that found in lean individuals. Controlled trials are needed to compare the lipid-lowering effects of ciprofibrate in groups of subjects defined by their adiposity or other markers of insulin resistance.Competing interests This study was supported by an educational grant provided by Sanofi-Synthelabo. It included the study expenses and it will cover the article processing charge. No other competing interest need to be declared
Competing interests
This study was supported by an educational grant provided by Sanofi-Synthelabo. It included the study expenses and it will cover the article processing charge. No other competing interest need to be declaredAuthor contributions CAAS participated in the design of the study, performed the statistical analysis and drafted the manuscript. AALV participated in the design of the study and in the preparation of the manuscript. FJGP participated in the design of the study and in the preparation of the manuscript. All other authors were responsible of the inclusion and follow-up of the study subjects. All authors read and approved the final manuscript.
Author contributions
CAAS participated in the design of the study, performed the statistical analysis and drafted the manuscript. AALV participated in the design of the study and in the preparation of the manuscript. FJGP participated in the design of the study and in the preparation of the manuscript. All other authors were responsible of the inclusion and follow-up of the study subjects. All authors read and approved the final manuscript.


Background The consistent finding of higher prevalence of hypertension in US blacks compared to whites has led to speculation that African-origin populations are particularly susceptible to this condition. Large surveys now provide new information on this issue.
Background
The consistent finding of higher prevalence of hypertension in US blacks compared to whites has led to speculation that African-origin populations are particularly susceptible to this condition. Large surveys now provide new information on this issue.Methods Using a standardized analysis strategy we examined prevalence estimates for 8 white and 3 black populations (N = 85,000 participants).
Methods
Using a standardized analysis strategy we examined prevalence estimates for 8 white and 3 black populations (N = 85,000 participants).Results The range in hypertension prevalence was from 27 to 55% for whites and 14 to 44% for blacks.
Results
The range in hypertension prevalence was from 27 to 55% for whites and 14 to 44% for blacks.Conclusions These data demonstrate that not only is there a wide variation in hypertension prevalence among both racial groups, the rates among blacks are not unusually high when viewed internationally. These data suggest that the impact of environmental factors among both populations may have been under-appreciated.
Conclusions
These data demonstrate that not only is there a wide variation in hypertension prevalence among both racial groups, the rates among blacks are not unusually high when viewed internationally. These data suggest that the impact of environmental factors among both populations may have been under-appreciated.

Background Population surveys in the US from early in the last century have consistently documented higher blood pressures and related cardiovascular sequelae in blacks compared to whites [ 1 , 2 ]. The enormous attention focused on this observation has resulted in a dichotomous view of hypertension risk: whereby populations of African origin are considered more susceptible than all other continental groupings and a strong genetic hypothesis of inherent predisposition to hypertension among blacks has become the conventional wisdom [ 3 - 5 ]. Since this research has been limited primarily to the US, the generalizability of these conclusions is open to question. Data on the prevalence of hypertension in other genetically-related populations of African and European descent constitute important evidence but have so far not been considered in the debate. International comparative studies on hypertension have been seriously limited by the absence of a valid method of standardization. In the last decade, however, high quality population surveys have been conducted in a wide range of populations that used either careful internal standardization or sufficiently comparable methods [ 6 - 15 ]. We report here on the patterns of hypertension prevalence in a sample of 3 such surveys among blacks from Africa, the Caribbean and the US and 8 surveys among whites from the US, Canada and Europe.
Background
Population surveys in the US from early in the last century have consistently documented higher blood pressures and related cardiovascular sequelae in blacks compared to whites [ 1 , 2 ]. The enormous attention focused on this observation has resulted in a dichotomous view of hypertension risk: whereby populations of African origin are considered more susceptible than all other continental groupings and a strong genetic hypothesis of inherent predisposition to hypertension among blacks has become the conventional wisdom [ 3 - 5 ]. Since this research has been limited primarily to the US, the generalizability of these conclusions is open to question. Data on the prevalence of hypertension in other genetically-related populations of African and European descent constitute important evidence but have so far not been considered in the debate.International comparative studies on hypertension have been seriously limited by the absence of a valid method of standardization. In the last decade, however, high quality population surveys have been conducted in a wide range of populations that used either careful internal standardization or sufficiently comparable methods [ 6 - 15 ]. We report here on the patterns of hypertension prevalence in a sample of 3 such surveys among blacks from Africa, the Caribbean and the US and 8 surveys among whites from the US, Canada and Europe.Methods Study design Black populations were drawn from the International Collaborative Study on Hypertension (ICSHIB) and the National Health and Nutrition Survey III [ 6 , 16 ]. A primary report of ICSHIB demonstrated a gradient in hypertension risk from east to west, parallel to the gradient in socioeconomic development and associated lifestyle [ 6 ]. An extensive process of cross-standardization was incorporated into ICSHIB to ensure that measurement technique did not bias the survey results [ 7 ]. We subsequently identified surveys on hypertension conducted since 1986 that were national in scope in North America and Europe. Two North American and six European surveys were included, viz: US [ 8 ] and Canada, [ 9 ], England [ 10 ], Finland [ 11 ], Germany [ 12 ], Italy [ 13 ], Spain [ 14 ] and Sweden [ 15 ]. The US data from NHANES-III are available for public use through the National Center for Health Statistics [ 8 ]. Investigators in Canada and Europe were contacted and invited to join this project. More detailed methods for this component of the study were reported earlier [ 16 ]. In brief, after achieving consensus on the main goals and resolving the methodological issues, data collection forms were distributed. Each collaborator provided average gender- and age-specific data by 5-year age groups for BPs, body mass index (BMI), and counts of hypertensives by treatment and control status. A description of the key aspects of each survey, including the BP measurement procedure, was collected in a standardized format. The surveys that formed the basis of ICSHIB were conducted in localized communities by door-to-door screening [ 6 , 7 ]. In summary, individual communities were chosen on the basis of apparent representativeness and census data were obtained. Sampling was based on probability proportional to size and was structured to lead to a sample equally balanced by gender and age group across the 10-year age. The studies of the European-origin populations and African Americans were larger in scope [ 16 ]. Some were based on a random probability sample of the entire nation, while others were a series of regional samples; none were restricted mainly to a single province or sub-region within the country (Table  3 ). Collectively the studies enrolled 85,000 participants and the number of subjects in individual studies ranged from 1,800 to 23,000. Participation rates varied from 61% to 88%. Sampling was conducted mainly on population registries. Table 3 Hypertension Prevalence (%) among Persons 35–64 Years, in African- and European-Origin Populations * Total (%) Men (%) Women (%) African-Origin Populations Nigeria 13.5 13.9 13.1 Jamaica 28.6 23.4 31.8 US – Black 44.0 43.1 44.8 European-Origin Populations US – White 26.8 29.7 23.9 Canada 27.4 31.0 23.8 Italy 41.5 48.0 35.1 Sweden 38.4 44.8 32.0 England 41.7 46.9 36.5 Spain 46.8 49.0 44.6 Finland 48.6 55.7 41.6 Germany 55.3 60.2 50.4 * Age-adjusted Data collection methods The examination methods have been reported in detail previously [ 6 , 7 , 16 ]. In brief, the mercury sphygmomanometer was used for BP measurements in every country except England, where the Dinamap 8100 oscillometric device was used. All studies had at least 2 measurements and the 2 nd  BP from the clinic visit was used to create the mean for the age-gender groups, except for England where the 2 nd  home BP was used. Hypertension was defined as BP ≥ 140/90 mmHg or current use of antihypertensive medication. Data analysis BP, body mass index (BMI), and hypertension prevalence were calculated for 5-year age-gender groups and aggregated as the primary data file. To achieve maximum overlap we restricted the analysis to 35–74 years for age-specific estimates of BP and hypertension prevalence, and 35–64 years for age-adjusted results. In the US NHANES whites and blacks were analyzed separately with the appropriate weighting for population size. As previously reported, the prevalence estimates obtained for US blacks from ICSHIB were virtually identical to those from NHANES [ 6 ]; to enhance generalizability, however, we used the NHANES data to represent the US black population. Hypertension prevalence and control was age-adjusted by age-averaging the 5-year age groups combining the data for men and women. For comparison of all white vs. all black populations the mean BP's and prevalences were averaged, considering each country as a single unit (i.e., without weighting by population size).
Methods
Study design Black populations were drawn from the International Collaborative Study on Hypertension (ICSHIB) and the National Health and Nutrition Survey III [ 6 , 16 ]. A primary report of ICSHIB demonstrated a gradient in hypertension risk from east to west, parallel to the gradient in socioeconomic development and associated lifestyle [ 6 ]. An extensive process of cross-standardization was incorporated into ICSHIB to ensure that measurement technique did not bias the survey results [ 7 ]. We subsequently identified surveys on hypertension conducted since 1986 that were national in scope in North America and Europe. Two North American and six European surveys were included, viz: US [ 8 ] and Canada, [ 9 ], England [ 10 ], Finland [ 11 ], Germany [ 12 ], Italy [ 13 ], Spain [ 14 ] and Sweden [ 15 ]. The US data from NHANES-III are available for public use through the National Center for Health Statistics [ 8 ]. Investigators in Canada and Europe were contacted and invited to join this project. More detailed methods for this component of the study were reported earlier [ 16 ]. In brief, after achieving consensus on the main goals and resolving the methodological issues, data collection forms were distributed. Each collaborator provided average gender- and age-specific data by 5-year age groups for BPs, body mass index (BMI), and counts of hypertensives by treatment and control status. A description of the key aspects of each survey, including the BP measurement procedure, was collected in a standardized format. The surveys that formed the basis of ICSHIB were conducted in localized communities by door-to-door screening [ 6 , 7 ]. In summary, individual communities were chosen on the basis of apparent representativeness and census data were obtained. Sampling was based on probability proportional to size and was structured to lead to a sample equally balanced by gender and age group across the 10-year age. The studies of the European-origin populations and African Americans were larger in scope [ 16 ]. Some were based on a random probability sample of the entire nation, while others were a series of regional samples; none were restricted mainly to a single province or sub-region within the country (Table  3 ). Collectively the studies enrolled 85,000 participants and the number of subjects in individual studies ranged from 1,800 to 23,000. Participation rates varied from 61% to 88%. Sampling was conducted mainly on population registries. Table 3 Hypertension Prevalence (%) among Persons 35–64 Years, in African- and European-Origin Populations * Total (%) Men (%) Women (%) African-Origin Populations Nigeria 13.5 13.9 13.1 Jamaica 28.6 23.4 31.8 US – Black 44.0 43.1 44.8 European-Origin Populations US – White 26.8 29.7 23.9 Canada 27.4 31.0 23.8 Italy 41.5 48.0 35.1 Sweden 38.4 44.8 32.0 England 41.7 46.9 36.5 Spain 46.8 49.0 44.6 Finland 48.6 55.7 41.6 Germany 55.3 60.2 50.4 * Age-adjusted
Study design
Black populations were drawn from the International Collaborative Study on Hypertension (ICSHIB) and the National Health and Nutrition Survey III [ 6 , 16 ]. A primary report of ICSHIB demonstrated a gradient in hypertension risk from east to west, parallel to the gradient in socioeconomic development and associated lifestyle [ 6 ]. An extensive process of cross-standardization was incorporated into ICSHIB to ensure that measurement technique did not bias the survey results [ 7 ]. We subsequently identified surveys on hypertension conducted since 1986 that were national in scope in North America and Europe. Two North American and six European surveys were included, viz: US [ 8 ] and Canada, [ 9 ], England [ 10 ], Finland [ 11 ], Germany [ 12 ], Italy [ 13 ], Spain [ 14 ] and Sweden [ 15 ]. The US data from NHANES-III are available for public use through the National Center for Health Statistics [ 8 ]. Investigators in Canada and Europe were contacted and invited to join this project. More detailed methods for this component of the study were reported earlier [ 16 ]. In brief, after achieving consensus on the main goals and resolving the methodological issues, data collection forms were distributed. Each collaborator provided average gender- and age-specific data by 5-year age groups for BPs, body mass index (BMI), and counts of hypertensives by treatment and control status. A description of the key aspects of each survey, including the BP measurement procedure, was collected in a standardized format.The surveys that formed the basis of ICSHIB were conducted in localized communities by door-to-door screening [ 6 , 7 ]. In summary, individual communities were chosen on the basis of apparent representativeness and census data were obtained. Sampling was based on probability proportional to size and was structured to lead to a sample equally balanced by gender and age group across the 10-year age. The studies of the European-origin populations and African Americans were larger in scope [ 16 ]. Some were based on a random probability sample of the entire nation, while others were a series of regional samples; none were restricted mainly to a single province or sub-region within the country (Table  3 ). Collectively the studies enrolled 85,000 participants and the number of subjects in individual studies ranged from 1,800 to 23,000. Participation rates varied from 61% to 88%. Sampling was conducted mainly on population registries.Hypertension Prevalence (%) among Persons 35–64 Years, in African- and European-Origin Populations *Total (%)Men (%)Women (%)African-Origin PopulationsEuropean-Origin Populations* Age-adjustedData collection methods The examination methods have been reported in detail previously [ 6 , 7 , 16 ]. In brief, the mercury sphygmomanometer was used for BP measurements in every country except England, where the Dinamap 8100 oscillometric device was used. All studies had at least 2 measurements and the 2 nd  BP from the clinic visit was used to create the mean for the age-gender groups, except for England where the 2 nd  home BP was used. Hypertension was defined as BP ≥ 140/90 mmHg or current use of antihypertensive medication.
Data collection methods
The examination methods have been reported in detail previously [ 6 , 7 , 16 ]. In brief, the mercury sphygmomanometer was used for BP measurements in every country except England, where the Dinamap 8100 oscillometric device was used. All studies had at least 2 measurements and the 2 nd  BP from the clinic visit was used to create the mean for the age-gender groups, except for England where the 2 nd  home BP was used. Hypertension was defined as BP ≥ 140/90 mmHg or current use of antihypertensive medication.Data analysis BP, body mass index (BMI), and hypertension prevalence were calculated for 5-year age-gender groups and aggregated as the primary data file. To achieve maximum overlap we restricted the analysis to 35–74 years for age-specific estimates of BP and hypertension prevalence, and 35–64 years for age-adjusted results. In the US NHANES whites and blacks were analyzed separately with the appropriate weighting for population size. As previously reported, the prevalence estimates obtained for US blacks from ICSHIB were virtually identical to those from NHANES [ 6 ]; to enhance generalizability, however, we used the NHANES data to represent the US black population. Hypertension prevalence and control was age-adjusted by age-averaging the 5-year age groups combining the data for men and women. For comparison of all white vs. all black populations the mean BP's and prevalences were averaged, considering each country as a single unit (i.e., without weighting by population size).
Data analysis
BP, body mass index (BMI), and hypertension prevalence were calculated for 5-year age-gender groups and aggregated as the primary data file. To achieve maximum overlap we restricted the analysis to 35–74 years for age-specific estimates of BP and hypertension prevalence, and 35–64 years for age-adjusted results. In the US NHANES whites and blacks were analyzed separately with the appropriate weighting for population size. As previously reported, the prevalence estimates obtained for US blacks from ICSHIB were virtually identical to those from NHANES [ 6 ]; to enhance generalizability, however, we used the NHANES data to represent the US black population. Hypertension prevalence and control was age-adjusted by age-averaging the 5-year age groups combining the data for men and women. For comparison of all white vs. all black populations the mean BP's and prevalences were averaged, considering each country as a single unit (i.e., without weighting by population size).Results Patterns of blood pressure The age-averaged BPs and BMIs are presented for each survey, by gender, in Table  2 . It must be recognized that where treatment is common these data may understate the true values, although this effect is likely to be small when the population is considered as a whole. Trends in BP with age showed considerable heterogeneity within population groups of both continental ancestry (i.e. African and European) (Figures  1 ,  2 ). In rural Nigeria, mean BPs were low and rose only modestly with age (Figure  1 ). Intermediate levels of BP were observed in Jamaica, while the US blacks had higher BPs at all ages. As previously reported, whites in the US and Canada had substantially lower BPs over the entire life span than did the Europeans (Figure  2 ). For greater clarity, the age-specific patterns are presented for all black and all white groups combined (Figure  3 ). Table 2 Mean Systolic and Diastolic Blood Pressure and Body Mass Index among Persons 35–74 Years, in African- and European-Origin Populations* Total Sys / Dias Men Sys / Dias Women Sys / Dias BMI, All (mmHg) (mmHg) (mmHg) (kg/m2) African-Origin Populations Nigeria 121.5/72.4 122.2/73.0 121.0/71.9 22.9 Jamaica 122.9/71.7 122.5/72.0 123.2/71.5 27.0 US – Black 129.7/78.5 130.3/80.8 129.1/76.3 28.5 European-Origin Populations US – White 120.9/75.2 123.4/78.2 118.3/72.2 27.3 Canada 128.2/80.8 131.2/83.2 125.1/78.5 26.8 Italy 129.8/83.1 132.4/85.4 127.2/80.7 26.4 Sweden 130.6/80.9 133.0/83.4 128.3/78.4 26.5 England 135.0/77.2 137.3/80.3 132.7/74.2 27.1 Spain 131.4/83.2 132.3/83.9 130.5/82.5 27.4 Finland 134.3/83.8 136.9/86.0 131.6/81.5 27.1 Germany 138.0/86.4 139.5/88.5 137.3/84.3 27.3 * Age-adjusted Figure 1 Mean Systolic Blood Pressure, African Descent Populations; By Age Group Figure 2 Mean Systolic Blood Pressure, European Descent Populations; By Age Group Figure 3 Mean Systolic Blood Pressure, African and European Descent Populations; By Age Group Hypertension prevalence Hypertension prevalence, which accounts for the effect of treatment, follows a similar pattern although the east-west gradient among the African-origin groups is more consistent (Table  3 , Figure  4 ). Among the 14 populations, US blacks fall near the middle in terms of prevalence (mean prevalence = 37%, U.S. blacks = 44%). Among those above the mean, all but one is of European origin. Important differences are apparent in the gender-specific prevalence hypertension in these groups. Among Jamaican women hypertension was substantially more common than among Jamaican men (32% vs. 23%), and relative gender equality existed for US blacks. In Europe, however, the prevalence of hypertension was higher among men in every country (range 5–10%). Figure 4 Hypertension Prevalence (140/90 mmHg or Treatment), African and European Descent Populations; Ages 35–64, Age Adjusted Hypertension prevalence and obesity The only etiological factor on which standardized information was available was obesity, measured by its proxy BMI. The correlation between average BMI and hypertension prevalence was 0.6 (p < 0.01), all populations combined. Within the black populations the same correlation was observed between mean BMIs and hypertension prevalence (r = 0.6). Among whites, however, the relationship was weaker (r = 0.3). Of course, since obesity will be correlated with many other aspects of lifestyle, it is difficult to infer whether weight gain itself is playing a less important role in determining the variation among white populations. The contrasts noted above in hypertension prevalence by gender are consistent with the relative excess of obesity in women compared to men among Jamaicans and US blacks [ 2 , 6 ].
Results
Patterns of blood pressure The age-averaged BPs and BMIs are presented for each survey, by gender, in Table  2 . It must be recognized that where treatment is common these data may understate the true values, although this effect is likely to be small when the population is considered as a whole. Trends in BP with age showed considerable heterogeneity within population groups of both continental ancestry (i.e. African and European) (Figures  1 ,  2 ). In rural Nigeria, mean BPs were low and rose only modestly with age (Figure  1 ). Intermediate levels of BP were observed in Jamaica, while the US blacks had higher BPs at all ages. As previously reported, whites in the US and Canada had substantially lower BPs over the entire life span than did the Europeans (Figure  2 ). For greater clarity, the age-specific patterns are presented for all black and all white groups combined (Figure  3 ). Table 2 Mean Systolic and Diastolic Blood Pressure and Body Mass Index among Persons 35–74 Years, in African- and European-Origin Populations* Total Sys / Dias Men Sys / Dias Women Sys / Dias BMI, All (mmHg) (mmHg) (mmHg) (kg/m2) African-Origin Populations Nigeria 121.5/72.4 122.2/73.0 121.0/71.9 22.9 Jamaica 122.9/71.7 122.5/72.0 123.2/71.5 27.0 US – Black 129.7/78.5 130.3/80.8 129.1/76.3 28.5 European-Origin Populations US – White 120.9/75.2 123.4/78.2 118.3/72.2 27.3 Canada 128.2/80.8 131.2/83.2 125.1/78.5 26.8 Italy 129.8/83.1 132.4/85.4 127.2/80.7 26.4 Sweden 130.6/80.9 133.0/83.4 128.3/78.4 26.5 England 135.0/77.2 137.3/80.3 132.7/74.2 27.1 Spain 131.4/83.2 132.3/83.9 130.5/82.5 27.4 Finland 134.3/83.8 136.9/86.0 131.6/81.5 27.1 Germany 138.0/86.4 139.5/88.5 137.3/84.3 27.3 * Age-adjusted Figure 1 Mean Systolic Blood Pressure, African Descent Populations; By Age Group Figure 2 Mean Systolic Blood Pressure, European Descent Populations; By Age Group Figure 3 Mean Systolic Blood Pressure, African and European Descent Populations; By Age Group
Patterns of blood pressure
The age-averaged BPs and BMIs are presented for each survey, by gender, in Table  2 . It must be recognized that where treatment is common these data may understate the true values, although this effect is likely to be small when the population is considered as a whole. Trends in BP with age showed considerable heterogeneity within population groups of both continental ancestry (i.e. African and European) (Figures  1 ,  2 ). In rural Nigeria, mean BPs were low and rose only modestly with age (Figure  1 ). Intermediate levels of BP were observed in Jamaica, while the US blacks had higher BPs at all ages. As previously reported, whites in the US and Canada had substantially lower BPs over the entire life span than did the Europeans (Figure  2 ). For greater clarity, the age-specific patterns are presented for all black and all white groups combined (Figure  3 ).Mean Systolic and Diastolic Blood Pressure and Body Mass Index among Persons 35–74 Years, in African- and European-Origin Populations*Total Sys / DiasMen Sys / DiasWomen Sys / DiasBMI, AllAfrican-Origin PopulationsEuropean-Origin Populations* Age-adjustedHypertension prevalence Hypertension prevalence, which accounts for the effect of treatment, follows a similar pattern although the east-west gradient among the African-origin groups is more consistent (Table  3 , Figure  4 ). Among the 14 populations, US blacks fall near the middle in terms of prevalence (mean prevalence = 37%, U.S. blacks = 44%). Among those above the mean, all but one is of European origin. Important differences are apparent in the gender-specific prevalence hypertension in these groups. Among Jamaican women hypertension was substantially more common than among Jamaican men (32% vs. 23%), and relative gender equality existed for US blacks. In Europe, however, the prevalence of hypertension was higher among men in every country (range 5–10%). Figure 4 Hypertension Prevalence (140/90 mmHg or Treatment), African and European Descent Populations; Ages 35–64, Age Adjusted
Hypertension prevalence
Hypertension prevalence, which accounts for the effect of treatment, follows a similar pattern although the east-west gradient among the African-origin groups is more consistent (Table  3 , Figure  4 ). Among the 14 populations, US blacks fall near the middle in terms of prevalence (mean prevalence = 37%, U.S. blacks = 44%). Among those above the mean, all but one is of European origin. Important differences are apparent in the gender-specific prevalence hypertension in these groups. Among Jamaican women hypertension was substantially more common than among Jamaican men (32% vs. 23%), and relative gender equality existed for US blacks. In Europe, however, the prevalence of hypertension was higher among men in every country (range 5–10%).Hypertension prevalence and obesity The only etiological factor on which standardized information was available was obesity, measured by its proxy BMI. The correlation between average BMI and hypertension prevalence was 0.6 (p < 0.01), all populations combined. Within the black populations the same correlation was observed between mean BMIs and hypertension prevalence (r = 0.6). Among whites, however, the relationship was weaker (r = 0.3). Of course, since obesity will be correlated with many other aspects of lifestyle, it is difficult to infer whether weight gain itself is playing a less important role in determining the variation among white populations. The contrasts noted above in hypertension prevalence by gender are consistent with the relative excess of obesity in women compared to men among Jamaicans and US blacks [ 2 , 6 ].
Hypertension prevalence and obesity
The only etiological factor on which standardized information was available was obesity, measured by its proxy BMI. The correlation between average BMI and hypertension prevalence was 0.6 (p < 0.01), all populations combined. Within the black populations the same correlation was observed between mean BMIs and hypertension prevalence (r = 0.6). Among whites, however, the relationship was weaker (r = 0.3). Of course, since obesity will be correlated with many other aspects of lifestyle, it is difficult to infer whether weight gain itself is playing a less important role in determining the variation among white populations. The contrasts noted above in hypertension prevalence by gender are consistent with the relative excess of obesity in women compared to men among Jamaicans and US blacks [ 2 , 6 ].Discussion Comparisons of BP distributions across populations are made difficult by the requirement of comparability of the survey methods. In the last two decades, however, adoption of standardized protocols along with rigorous training have greatly improved the quality of epidemiological studies of hypertension [ 6 , 17 - 19 ]. A number of countries now conduct recurring national surveys that monitor both secular trends and regional variation within the country [ 10 - 12 , 19 , 20 ]. While independent surveys from the same base population had given divergent results in the past, at least two recent single-community studies conducted in the US provided estimates virtually identical to NHANES [ 21 , 22 ]. Although this evidence does not diminish the requirement of careful assessment of survey methodology before making comparisons, it does demonstrate that reliable information can be obtained from independent studies. The data presented here demonstrate a two-fold variation in prevalence of hypertension in both European- and African-origin populations. The prevalences are similar in blacks in the US and whites in Europe, although important gender differences are apparent. Although not a systematic sample, the populations that are included generally reflect the characteristic social setting in which these groups are found around the world. Summed across all groups, the white populations on average have a substantially higher burden of hypertension. This result can be attributed in large part to the inclusion of several black samples from developing countries where risk factors for hypertension are presently at a lower level. In the only head-to-head comparison within the same survey, US blacks have a prevalence that is 50% higher than among whites. Data from the UK, including the national survey, also demonstrate higher BPs and more hypertension among blacks of Caribbean and African descent [ 23 - 27 ]. On the whole, however, the published literature on racial disparities in hypertension from the UK is less consistent than in the US, where essentially every study has reported higher rates among blacks [ 28 ]. Surveys from Cuba, Trinidad and Brazil have also shown a smaller black-white gradient in BP than found in North America [ 29 - 31 ]. Are these findings merely artifactual, reflecting either methodological error or the sampling process? The most unexpected features of the data presented here are the high rates of hypertension in Europe, when contrasted to whites in Canada and the US. These results have been reported in greater detail in an earlier publication [ 16 ]. It is beyond the usual standard of statistical significance for the six European surveys to be higher by chance than both of those in North America (p < 0.05). As previously demonstrated, mortality rates for stroke – the most sensitive vital statistics indicator of uncontrolled high BP – are strongly correlated with the prevalence of hypertension among these countries ('r' = 0.8) [ 16 ]. Although the data are more limited, hypertension appears to be even more common in Eastern Europe [ 32 - 34 ]. In a comparison of Pol-MONICA with the US-based ARIC study, systolic BPs in Poland were 20 mmHg higher than in the US [ 3 ]. The primary purpose of this analysis was to provide descriptive results and very limited information was available on factors that might explain the findings we observed. The gradient among the black populations is consistent with the transition to an industrialized lifestyle and is thereby collinear with most known risk factors [ 6 ]. BMI is serving as an effective proxy for this relationship, although its independent contribution cannot be quantified. The explanation of the European-North American contrasts among the white populations is not as apparent. As we have discussed elsewhere, either known risk factors other than obesity are having a larger impact at the population level than usually appreciated, or unknown factors are at work [ 16 ]. In either case, further examination of this question seems justified. Treatment guidelines and practice patterns vary widely among these countries [ 16 - 19 ]. Widespread treatment could, of course, alter the mean BPs in a population, although this effect would be confined to persons over 55 where hypertension is common. The US has the highest rate of treatment, with about 25% of hypertensives controlled, compared to 10% in Europe and less than 1% in Africa (with hypertension defined as 140/90 mmHg)[ 16 ]. Any biases that would be introduced into the cross-national comparisons by differential treatment and control are insufficient to alter the primary conclusions, however. The virtual absence of treatment in rural Africa would mean that the natural distribution has essentially been observed unaltered. The effect of treatment in the US or Canada would not be apparent in younger individuals, where contrasts in BPs with Europe and Africa are equally large. If the North American-European contrasts are occurring in genetically homogeneous populations, large environmental influences must be at work that are not apparent on the surface. A similar process could be taking place across the social environments into which persons of African origin are assorted within societies such as the US and the UK. The debate over inherent susceptibility cannot be resolved with these data since neither the genetic nor the environmental influences can be held constant, allowing a test of the relative influence of the other factor. In fact, the question of inherent susceptibility is probably non-testable under any circumstances [ 35 - 37 ]. While the assumption is often made that contrasting environmental influences between blacks and whites can be adjusted by using proxy measures such as education, that assumption does not hold up under close examination [ 38 ]. Perhaps more to the point, however, these data demonstrate that the consistent emphasis given to the genetic elements of the racial contrasts may be a distraction from the more relevant issue of defining and intervening on the preventable causes of hypertension, which are likely to have a similar impact regardless of ethnic and racial background [ 39 ]. Once the problem of ethnic/racial contrasts is characterized more closely as a special instance of environmental influences at the population level, it could become more tractable in both the realms of research and practice.
Discussion
Comparisons of BP distributions across populations are made difficult by the requirement of comparability of the survey methods. In the last two decades, however, adoption of standardized protocols along with rigorous training have greatly improved the quality of epidemiological studies of hypertension [ 6 , 17 - 19 ]. A number of countries now conduct recurring national surveys that monitor both secular trends and regional variation within the country [ 10 - 12 , 19 , 20 ]. While independent surveys from the same base population had given divergent results in the past, at least two recent single-community studies conducted in the US provided estimates virtually identical to NHANES [ 21 , 22 ]. Although this evidence does not diminish the requirement of careful assessment of survey methodology before making comparisons, it does demonstrate that reliable information can be obtained from independent studies.The data presented here demonstrate a two-fold variation in prevalence of hypertension in both European- and African-origin populations. The prevalences are similar in blacks in the US and whites in Europe, although important gender differences are apparent. Although not a systematic sample, the populations that are included generally reflect the characteristic social setting in which these groups are found around the world. Summed across all groups, the white populations on average have a substantially higher burden of hypertension. This result can be attributed in large part to the inclusion of several black samples from developing countries where risk factors for hypertension are presently at a lower level. In the only head-to-head comparison within the same survey, US blacks have a prevalence that is 50% higher than among whites. Data from the UK, including the national survey, also demonstrate higher BPs and more hypertension among blacks of Caribbean and African descent [ 23 - 27 ]. On the whole, however, the published literature on racial disparities in hypertension from the UK is less consistent than in the US, where essentially every study has reported higher rates among blacks [ 28 ]. Surveys from Cuba, Trinidad and Brazil have also shown a smaller black-white gradient in BP than found in North America [ 29 - 31 ].Are these findings merely artifactual, reflecting either methodological error or the sampling process? The most unexpected features of the data presented here are the high rates of hypertension in Europe, when contrasted to whites in Canada and the US. These results have been reported in greater detail in an earlier publication [ 16 ]. It is beyond the usual standard of statistical significance for the six European surveys to be higher by chance than both of those in North America (p < 0.05). As previously demonstrated, mortality rates for stroke – the most sensitive vital statistics indicator of uncontrolled high BP – are strongly correlated with the prevalence of hypertension among these countries ('r' = 0.8) [ 16 ]. Although the data are more limited, hypertension appears to be even more common in Eastern Europe [ 32 - 34 ]. In a comparison of Pol-MONICA with the US-based ARIC study, systolic BPs in Poland were 20 mmHg higher than in the US [ 3 ].The primary purpose of this analysis was to provide descriptive results and very limited information was available on factors that might explain the findings we observed. The gradient among the black populations is consistent with the transition to an industrialized lifestyle and is thereby collinear with most known risk factors [ 6 ]. BMI is serving as an effective proxy for this relationship, although its independent contribution cannot be quantified. The explanation of the European-North American contrasts among the white populations is not as apparent. As we have discussed elsewhere, either known risk factors other than obesity are having a larger impact at the population level than usually appreciated, or unknown factors are at work [ 16 ]. In either case, further examination of this question seems justified.Treatment guidelines and practice patterns vary widely among these countries [ 16 - 19 ]. Widespread treatment could, of course, alter the mean BPs in a population, although this effect would be confined to persons over 55 where hypertension is common. The US has the highest rate of treatment, with about 25% of hypertensives controlled, compared to 10% in Europe and less than 1% in Africa (with hypertension defined as 140/90 mmHg)[ 16 ]. Any biases that would be introduced into the cross-national comparisons by differential treatment and control are insufficient to alter the primary conclusions, however. The virtual absence of treatment in rural Africa would mean that the natural distribution has essentially been observed unaltered. The effect of treatment in the US or Canada would not be apparent in younger individuals, where contrasts in BPs with Europe and Africa are equally large.If the North American-European contrasts are occurring in genetically homogeneous populations, large environmental influences must be at work that are not apparent on the surface. A similar process could be taking place across the social environments into which persons of African origin are assorted within societies such as the US and the UK. The debate over inherent susceptibility cannot be resolved with these data since neither the genetic nor the environmental influences can be held constant, allowing a test of the relative influence of the other factor. In fact, the question of inherent susceptibility is probably non-testable under any circumstances [ 35 - 37 ]. While the assumption is often made that contrasting environmental influences between blacks and whites can be adjusted by using proxy measures such as education, that assumption does not hold up under close examination [ 38 ]. Perhaps more to the point, however, these data demonstrate that the consistent emphasis given to the genetic elements of the racial contrasts may be a distraction from the more relevant issue of defining and intervening on the preventable causes of hypertension, which are likely to have a similar impact regardless of ethnic and racial background [ 39 ]. Once the problem of ethnic/racial contrasts is characterized more closely as a special instance of environmental influences at the population level, it could become more tractable in both the realms of research and practice.Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' contributions RC, KWM, AL and JB were responsible for study concept, design and supervision. RC, KWM, JB, SG, MJ, AA, TF MK, PP, BS and MT were involved in data acquisition. RC, KWM, JB, MJ, PP and AL were responsible for analysis and interpretation of data. RC and KWM drafted the manuscript. RC, JB, SG, AL, AA, TF, MJ, MK, PP, BS and MT were involved in critical revision of the manuscript for important intellectual content. Statistical expertise was provided by MJ. Administrative, technical and material support was provided by KWM, MK, and BS. Table 1 Characteristics of the Surveys Country Survey Yr(s) Population N Male (%) Participation Rate (%) Age Range Sampling Method* Nigeria 1991–93 Local 1931 45 NA 25–74 Multistage, address Jamaica 1993–95 Local 2573 41 65 25–74 Multistage, address USA, NHANES Black 1988–94 National 5283 45 82 18–80+ Multistage, population registry Canada 1986–92 National 23129 49 77.5 18–74 Multistage, medical insurance registries England 1998 National 11884 45 87.5 16–80+ Multistage, post code address Finland 1997 National 7064 47 72 25–64 Population registry Germany 1997–99 National 7047 49 61.4 18–79 Population registry Italy 1998 National 8233 50 - 35–74 Multistage, population registry Spain 1990 National 2021 40 73 35–65 Multistage, national registry Sweden 1999 Regional 1823 49 72 25–74 Population registry USA NHANES White 1988–94 National 7252 46 82 18–80+ Multistage, population registry * All stratified sampling methods
Authors' contributions
RC, KWM, AL and JB were responsible for study concept, design and supervision. RC, KWM, JB, SG, MJ, AA, TF MK, PP, BS and MT were involved in data acquisition. RC, KWM, JB, MJ, PP and AL were responsible for analysis and interpretation of data. RC and KWM drafted the manuscript. RC, JB, SG, AL, AA, TF, MJ, MK, PP, BS and MT were involved in critical revision of the manuscript for important intellectual content. Statistical expertise was provided by MJ. Administrative, technical and material support was provided by KWM, MK, and BS.Characteristics of the SurveysCountrySurvey Yr(s)PopulationNMale (%)Participation Rate (%)Age RangeSampling Method** All stratified sampling methodsPre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here: