Metabolic Risk Factors For Coronary Heart Disease Research Articles

Marital status and genetic liability independently predict coronary heart disease incidence.

Married individuals have a lower coronary heart disease (CHD) risk than non-married, but the mechanisms behind this are not fully understood. We analyzed whether genetic liability to CHD may affect these associations. Marital status, a polygenic score of CHD (PGS-CHD), and other risk factors for CHD were measured from 35,444 participants (53% female) in Finnish population-based surveys conducted between 1992 and 2012. During the register-based follow-up until 2020, there were 2439 fatal and non-fatal incident CHD cases. The data were analyzed using linear and Cox regression models. Divorced and cohabiting men and women had a higher genetic risk of CHD than married individuals, but the difference was very small (0.023-0.058 standard deviation of PGS-CHD, p-values 0.011-0.429). Both marital status and PGS-CHD were associated with CHD incidence, but the associations were largely independent. Adjusting for behavioral and metabolic risk factors for CHD explained part of these associations (11-20%). No interaction was found between marital status and PGS-CHD for CHD incidence. We showed minor differences between the marital status categories in PGS-CHD and demonstrated that marital status and genetic liability predicted CHD incidence largely independently. This emphasizes the need to measure multiple risk factors when predicting CHD risk.

Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study.

Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention. To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with -0.07 (95% confidence interval, -0.01 to -0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04). Overall, our findings support a role of insulin as a mediator on the causal pathway from shorter telomeres to CHD pathogenesis.

Long‐term Effects of Large‐volume Liposuction on Metabolic Risk Factors for Coronary Heart Disease

Abdominal obesity is associated with metabolic risk factors for coronary heart disease (CHD). Although we previously found that using liposuction surgery to remove abdominal subcutaneous adipose tissue (SAT) did not result in metabolic benefits, it is possible that postoperative inflammation masked the beneficial effects. Therefore, this study provides a long-term evaluation of a cohort of subjects from our original study. Body composition and metabolic risk factors for CHD, including oral glucose tolerance, insulin resistance, plasma lipid profile, and blood pressure were evaluated in seven obese (39 +/- 2 kg/m(2)) women before and at 10, 27, and 84-208 weeks after large-volume liposuction. Liposuction surgery removed 9.4 +/- 1.8 kg of body fat (16 +/- 2% of total fat mass; 6.1 +/- 1.4 kg decrease in body weight), primarily from abdominal SAT; body composition and weight remained the same from 10 through 84-208 weeks. Metabolic endpoints (oral glucose tolerance, homeostasis model assessment of insulin resistance, blood pressure and plasma triglyceride (TG), high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)-cholesterol concentrations) obtained at 10 through 208 weeks were not different from baseline and did not change over time. These data demonstrate that removal of a large amount of abdominal SAT by using liposuction does not improve CHD metabolic risk factors associated with abdominal obesity, despite a long-term reduction in body fat.

Calorie restriction or exercise: effects on coronary heart disease risk factors. A randomized, controlled trial

Coronary heart disease (CHD) risk factors and the risk of CHD increase with increased adiposity. Fat loss induced by negative energy balance improves all metabolic CHD risk factors. To determine whether fat loss induced by long-term calorie restriction (CR) or increased energy expenditure induced by exercise (EX) has different effects on CHD risk factors in nonobese subjects, we conducted a 1-yr controlled trial involving 48 nonobese subjects who were randomly assigned to one of three groups: CR, 20% CR diet (n = 18); EX, 20% increase in energy expenditure through daily exercise with no increase in energy intake (n = 18); or HL, healthy lifestyle guidelines (n = 10). Subjects were 29 women and 17 men aged 57 +/- 3 yr, with BMI 27.3 +/- 2.0 kg/m(2). Assessments included total body fat by DEXA, lipoproteins, blood pressure, HOMA-IR, C-reactive protein (CRP), and estimated 10-yr CHD risk score. Body fat decreased by 6.3 +/- 3.8 kg in CR, 5.6 +/- 4.4 kg in EX, and 0.4 +/- 1.7 kg in HL, which corresponded to reductions of 24.9, 22.3, and 1.2% of baseline body fat mass, respectively. These CR- and EX-induced energy deficits were accompanied by reductions in most of the major CHD risk factors, including plasma LDL-cholesterol, total cholesterol/HDL ratio, HOMA-IR index, and CRP concentrations that were similar in the two intervention groups. Data from the present study provide evidence that CR- and EX-induced negative energy balance result in substantial and similar improvements in the major risk factors for CHD in normal-weight and overweight middle-aged adults.

HRT and the primary prevention of cardiovascular disease

Observational studies have consistently shown a benefit of hormone replacement therapy (HRT) on coronary heart disease (CHD), but some randomised studies have not shown any significant effect. Thus questions still remains as to whether HRT is beneficial for CHD, and in whom this benefit might be achieved. The biological effects of oestrogen on the cardiovascular system have been extensively studied, and beneficial effects on metabolic CHD risk factors, as well as on arterial function and on surrogate clinical markers of CHD, have been demonstrated. Thus it seems implausible that HRT should not benefit CHD in postmenopausal women. Most randomised trials using clinical outcomes have studied just one dose of one HRT regimen, a dose inappropriately high with the average starting age of the participants being in their mid-60s. The observational population studies largely comprise women starting on HRT at appropriate dose around the age of menopause, i.e. early 50s. In fact, it was the older women in the randomised trials that failed to show benefit, whereas there was a trend to benefit in the younger ones for whom the starting dose of HRT was appropriate. Furthermore, a pilot study of lower dose HRT in older women did not show any cardiovascular harm. Inappropriately high doses of oestrogen could cause cardiovascular harm due to transient disturbances in thrombogenesis and vascular remodelling. Whilst the greatest CHD benefit may be seen by starting HRT in the early postmenopause, this does not exclude benefit in older women given appropriate low dose therapy.

Effect of lifestyle intervention on metabolic coronary heart disease risk factors in obese older adults

Coronary heart disease (CHD) risk factors increase with age and body mass index (BMI; in kg/m2). However, whether lifestyle intervention ameliorates metabolic CHD risk factors in obese older adults is unknown. The objective was to determine whether lifestyle intervention improves metabolic CHD risk factors in obese older adults. A 6-mo outpatient randomized controlled trial was conducted in obese (BMI >or= 30) older (>or=65 y) adults randomly assigned to diet and exercise therapy (treatment group; n = 17) or no therapy (control group; n = 10). The main outcomes were CHD risk factors. Body weight decreased by 8.4% (8.2 kg) in the treatment group; weight did not change significantly (0.7 kg) in the control group (P < 0.001 between groups). Changes between the control and treatment groups, respectively, in waist circumference (1 and -10 cm), plasma glucose (4 and -4 mg/dL), serum triacylglycerols (0 and -45 mg/dL), and systolic (-2 and -10 mm Hg) and diastolic (0 and -8 mm Hg) blood pressure were different (P < 0.05 for all). The number of subjects with the metabolic syndrome decreased by 59% in the treatment group but did not change significantly in the control group (P < 0.05). Serum free fatty acids increased by 10 micromol/L in the control group and decreased by 99 micromol/L in the treatment group (P < 0.05). Changes between the control and treatment groups, respectively, in C-reactive protein (0.8 and -2.5 mg/L) and interleukin 6 (1.6 and -2.4 pg/mL) were different (P < 0.05 for both). Lifestyle intervention decreases multiple metabolic CHD risk factors simultaneously in obese older adults.

Effect of Short‐Term Pritikin Diet Therapy on the Metabolic Syndrome

The Pritikin Program (Aventura, FL) involves the use of a very-low-fat, low-sodium, high-fiber diet and exercise to decrease the risk of coronary heart disease (CHD). This study evaluated the effect of short-term Pritikin therapy on the metabolic risk factors for CHD in patients with the metabolic syndrome. Sixty-seven subjects who had the metabolic syndrome and attended the Pritikin Longevity Center & Spa for 12-15 days were studied. Short-term Pritikin therapy improved most CHD risk factors: body mass index decreased by 3% (P<.001); systolic and diastolic blood pressure, and serum glucose and low-density lipoprotein cholesterol concentrations decreased by 10%-15% (P<.001); serum triglyceride concentration decreased by 36% (P<.001); and 37% of subjects no longer met National Cholesterol Education Program criteria for the metabolic syndrome. Serum high-density lipoprotein cholesterol, however, decreased by 3% (P<.05). These data demonstrate that brief treatment with a very-low-fat, low-sodium, high-fiber diet and regular exercise simultaneously improves multiple CHD risk factors in patients with the metabolic syndrome.

Adiposity measures and their relationship with metabolic risk factors for coronary heart disease in Bengalee Hindu men of Kolkata, India

The aim of the present study was to investigate the associations of generalized and central adiposity with established metabolic risk factors for coronary heart disease (CHD) among Bengalee Hindu men of Kolkata, India. A cross-sectional study of 212 Bengalee Hindu men resident in Kolkata, India, was undertaken utilizing four measures of adiposity: body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and conicity index (CI). Total cholesterol (TC), high density (HDL-C), low density (LDL-C) and very low density (VLDL-C) cholesterol lipoproteins, fasting blood glucose (FBG) and fasting triglyceride (FTG) levels were recorded. Results revealed that BMI did not have significant correlation with any of the metabolic variables. The Pearson correlation coefficients (r) of the central adiposity measures (WC, WHR and CI) were similar. WC, WHR and CI were significantly correlated (except WC and TC) with TC, VLDL-C, FBG and FTG. However, HDL-C and LDL-C did not show significant correlation with WC, WHR and CI. Regression analyses revealed that WC, WHR and CI had significant impact on TC, VLDL-C, FBG and FTG. All three measures of central adiposity had similar effect. This significant effect remained essentially the same even after controlling for BMI. In conclusion, the present investigation revealed that among Bengalee Hindu men, any one of these three measures (WC, WHR and CI) can be used in cross-sectional epidemiological studies dealing with the relationship of central adiposity and metabolic risk factors for CHD.

Visceral adipose tissue cutoffs associated with metabolic risk factors for coronary heart disease in women.

This study determined whether there is a critical level of visceral adipose tissue (VAT) associated with elevated coronary heart disease (CHD) risk factors in a cohort of women >45 years of age. Measurements of body composition (dual-energy X-ray absorptiometry), body fat distribution (computed tomography), fasting and 2-h postprandial (75-g) glucose concentrations, and fasting lipoprotein lipid and insulin concentrations were performed in 233 perimenopausal (9%) and postmenopausal women (age 59 +/- 6 years, 79% Caucasian, 16% on hormone replacement therapy). Women in the lowest VAT quintile (< or =105 cm(2)) had higher concentrations of HDL and HDL(2) cholesterol, lower LDL/HDL cholesterol ratios and triglyceride concentrations, and lower fasting glucose and insulin concentrations than women in the remaining four quintiles (P values <0.05-0.001). Women in the second lowest VAT quintile (106-139 cm(2)) had higher HDL and HDL(2) cholesterol and lower LDL/HDL ratios than women with a VAT > or =163 cm(2) (P < 0.05). Logistic regression analyses showed that women with a VAT of 106-162 cm(2) are 2.5 times more likely to have a low HDL cholesterol (P < 0.05), while women with a VAT > or =163 cm(2) are 5.5 times more likely to have a low HDL cholesterol (P < 0.01) and approximately 4.0 times more likely to have a high LDL/HDL ratio (P < 0.05) compared with women with a VAT < or =105 cm(2). Women with a VAT > or =163 cm(2) are at a higher risk of having impaired glucose tolerance (P < 0.01). A VAT > or =106 cm(2) is associated with an elevated risk, and a VAT > or =163 cm(2) with an even greater risk, for these metabolic CHD risk factors compared with women with a VAT < or =105 cm(2). These values may prove useful for defining "visceral obesity" and for identifying women most likely to benefit from preventative interventions.

Effects of Radiation on Fatty Liver and Metabolic Coronary Risk Factors among Atomic Bomb Survivors in Nagasaki

In order to clarify the basic mechanism(s) linking radiation exposure and coronary heart disease (CHD), we here collected ultrasonographic data on fatty liver and measured levels of metabolic CHD risk factors from November 1990 through October 1992 in 1,517 Nagasaki atomic bomb survivors (575 men and 942 women). Using a cross-sectional study design, we examined the effects of radiation dose on fatty liver and CHD risk factors by means of a multiple logistic regression model. Fatty liver was related to the metabolic CHD risk factors associated with insulin resistance syndrome: obesity, hypertension, hypercholesterolemia, low high density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, and abnormal glucose metabolism. Radiation dose was positively related to fatty liver, low HDL-cholesterol, and hypertriglyceridemia, whereas it had no effects on obesity, hypertension, hypercholesterolemia, or abnormal glucose metabolism. The present results suggested that radiation dose was related to 1) fatty liver, which clustered the metabolic CHD risk factors associated with insulin resistance syndrome and 2) atherogenic lipid profiles. It is suggested that these associations are involved in the basic mechanism(s) linking radiation exposure and CHD.

Determinants of haemostatic risk factors for coronary heart disease in obese children and adolescents.

To investigate the contribution of serum lipids, parameters of glucose metabolism, body composition and cardiovascular fitness to the variance of several haemostatic risk factors for coronary heart disease (CHD) in obese children and adolescents. Forty-two healthy, obese children and adolescents (20 male, 22 female, age 12.6 +/- 3.2y; body mass index (BMI), 30.4 +/- 5.3 kg/m2), were screened for haemostatic and metabolic risk factors for CHD. Thirty-five of the participants (18 male, age 13.5 +/- 2.9y; BMI, 29.9 +/-4.5kg/m2; 17 female, age 12.8+/-2.1 y, BMI, 31.1 +/- 5.3 kg/m2) were assessed for cardiovascular fitness by means of incremental cycle ergometer exercise. After adjustment for age, fat mass correlated significantly with plasminogen activator inhibitor-1 antigen (PAI-1-Ag) in boys and girls and factor VIIc only in girls. Children with lower power output (< or = 2.77W/kg) showed significantly higher values for factor VIIc, fibrinogen and tissue-type plasminogen activator antigen (tPA-Ag). Neither body composition nor cardiovascular fitness contributed independently to the variance of the determined haemostatic risk factors, except PAI-1-Ag, which has been shown to be determined by fat mass. In multiple linear regression analysis, triglycerides and PAI-1-Ag explained significant independent proportions of the variance of tPA-Ag. Factor VIIc was explained by C-peptide, insulin and fibrinogen. Von Willebrand factor antigen (vWF-Ag) was significantly related to glucose and insulin. The results suggest that in obese children and adolescents the haemostatic risk factors factor VIIc, vWF-Ag and tPA-Ag are mainly determinated by plasma insulin and triglyceride concentrations, but are primarily independent of body composition and cardiovascular fitness.

Insulin is an independent correlate of plasma homocysteine levels in obese children and adolescents.

The aim of the study was to investigate whether anthropometric and metabolic risk factors for coronary heart disease (CHD) contribute to the variation in homocysteine levels in obese children and adolescents. A total of 84 children and adolescents were assessed for fasting total homocysteine, methylenetetrahydrofolate reductase polymorphism (C677T mutation), folate and vitamin B12 status, and anthropometric and metabolic risk factors for CHD. No significant sex differences were found for all available anthropometric and metabolic characteristics except for homocysteine, which was significantly higher in boys than in girls (7.1 vs. 6.3 micromol/l; P<0.05). After adjustment for age and sex, homocysteine correlated significantly with BMI, fat mass, percentage of fat mass, and insulin and showed an inverse correlation with folate levels. Homocysteine did not correlate with vitamin B12; total cholesterol; LDL, HDL, and VLDL; triglycerides; and glucose. BMI and fat mass correlated significantly with insulin and showed a significant inverse correlation with folate. We found no association between homocysteine and the C677T mutation. In multiple regression analyses, insulin was found to be the main correlate of homocysteine. Our study demonstrates for the first time that insulin is a main correlate of homocysteine in obese children and adolescents and suggests that fat mass-associated hyper-insulinism may contribute to impairment of homocysteine metabolism in childhood obesity

Ambulatory Blood Pressure and Risk Factors for Coronary Heart Disease in Black and Indian Medical Students

Coronary heart disease (CHD) has reached 'epidemic' proportions in South Africa. CHD is uncommon in the black population of South Africa, yet the prevalence of hypertension in the adult black population is high. This study compared the blood pressure profile in 154 medical students of which 83 were Indians (1), 71 were black (B), 87 were male (50 I, 37 B), and 67 were female (33 I, 34 B) age 21 (SD+/-1.6), using the cuff method and 24 h ambulatory blood pressure monitoring (ABPM). All students underwent ABPM. Biochemical studies for CHD risk factors were done. Electrocardiography (ECG) was performed in all participants and echocardiography in 90. ABPM showed that black students had higher systolic and diastolic blood pressure throughout the day, night and critical time periods compared with the Indian students. Blood pressure load was higher in black (40.8%) than in Indian participants (29.6%; P<0.05) and there was less dipping at night Left ventricular mass was significantly higher in black than in Indian participants (29.6%; P<0.05) and there was less dipping at night. Left ventricular mass was significantly higher in black than in Indian participants. Risk factors leading to CHD were more common in Indian than in black participants. Those with borderline hypertension (blood pressure > or = 130/85 and < or = 140/90 mmHg) had statistically higher serum triglyceride and left ventricular mass than normotensives. Young black people had higher blood pressure readings than young Indian participants in the absence of metabolic abnormalities and had greater cardiac involvement Borderline hypertension is not innocuous. Metabolic risk factors for CHD in Indian people are apparent at an early age. This study emphasizes the need for prevention of risk factors leading to CHD at an early age.

Influence of body fatness on the coronary risk profile of physically active postmenopausal women

We have shown previously that endurance-trained postmenopausal runners demonstrate more favorable coronary heart disease (CHD) risk factors compared with age-matched sedentary women. However, the runners exhibited higher levels of physical activity and lower levels of body fatness, both of which can influence CHD risk factors. To gain insight into the influence of body fatness per se, we studied 38 postmenopausal healthy women: 10 swimmers, 10 runners, and nine obese and nine leaner sedentary subjects matched for age, hormone replacement use, and years postmenopause. Swimmers and runners were further matched for exercise training volume (4.5 ± 0.2 v 4.6 ± 0.6 h/wk) and relative competitive performance (79% ± 5% v 77 ± 3% of age-adjusted world record). Maximal oxygen consumption (V̇o 2max) on the treadmill was lower ( P < .01) in swimmers versus runners. Body mass (65.0 ± 2.0 v 59.0 ± 1.3 kg), percent body fat (29% ± 2% v 23% ± 2%), and waist circumference (79 ± 3 v 71 ± 1 cm) were greater ( P < .01) in swimmers than in runners. There were no significant differences in total caloric intake or dietary composition between swimmers and runners. Insulin sensitivity (via Bergman's minimal model) and fasting plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesteorl (LDL-C), triglyceride (TG), glucose, and plasminogen activator inhibitor-1 (PAI-1) activity were not different between the groups. However, plasma high-density lipoprotein cholesterol (HDL-C), HDL 2-C, HDL-C/TC, insulin, fibrinogen, fibrin D-dimer, PAI antigen, tissue plasminogen activator (t-PA) activity, and t-PA antigen levels all were less favorable ( P < .05) in swimmers versus runners. Daytime, nighttime, and 24-hour systolic blood pressure (SBP) was 6 to 10 mm Hg higher in swimmers compared with runners, but resting blood pressure, 24-hour blood pressure load, and blood pressure variability were not significantly different. Stepwise regression showed that measures of body fatness were the primary independent determinants of most of the metabolic CHD risk factors. When analysis of covariance (ANCOVA) was performed with body fatness as a covariate, differences in CHD risk factors between swimmers and runners were abolished( P = .18 to .90). We conclude that among endurance-trained postmenopausal women matched for training volume and competitive eliteness, higher total and abdominal body fatness is, in general, associated with a less favorable metabolic CHD risk profile. Thus, high levels of habitual aerobic exercise do not appear to negate the deleterious effects of diposity on the coronary risk profile of healthy middle-aged and older women.

The glycolytic pathway to coronary heart disease: A hypothesis

Coronary heart disease (CHD) is pathogenetically linked to numerous metabolic disturbances. These are inextricably interrelated, constituting identifiable clusters or syndromes of cardiovascular risk. Prominent among these is the insulin resistance syndrome, whose components, including hyperuricemia, have all been linked to CHD pathogenesis. Many mechanisms have been put forward to account for the emergence of this syndrome, but none offer a satisfactory explanation for the involvement of hyperuricemia. Possible explanations relate to the observation of glycolytic disturbances in insulin-resistant and hyperuricemic states. This might be expected from the fact that uric acid production is linked to glycolysis and that glycolysis is controlled by insulin. Phosphoribosylpyrophosphate (PPRP) is an important metabolite in this respect. Its availability depends on ribose-5-phosphate (R-5-P), the production of which is governed by glycolytic flux. Diversion of glycolytic intermediates toward R-5-P, PPRP, and uric acid will follow if there is diminished activity of glyceraldehyde-3-phosphate dehydrogenase (GA3PDH), which is regulated by insulin. Serum triglyceride concentrations may also increase, as might be expected from accumulation of glycerol-3-phosphate. Thus, intrinsic defects in GA3PDH and a loss of its responsiveness to insulin, by causing accumulation of glycolytic intermediates, may explain the association between insulin resistance, hyperuricemia, and hypertriglyceridemia. This scenario raises the possibility that disturbances of a single glycolytic enzyme may be pivotal in the modulation of metabolic risk factors for CHD.

Hormone replacement therapy and the cardiovascular system. Nonlipid effects.

Coronary heart disease (CHD) is the leading cause of death in women, and the risk of this disease rises markedly after loss of ovarian function. Hormone replacement therapy (HRT) can reduce the incidence of CHD in postmenopausal women by 50%. HRT causes changes in lipids and lipoproteins, but it is now clear that many other effects of gonadal steroid hormones have important influences on the cardiovascular system. These nonlipid effects include a variety of changes in other metabolic risk factors for CHD, as well as direct arterial effects. Insulin resistance and hyperinsulinaemia may be pivotal disturbances in the pathogenesis of CHD. Estradiol reverses the effects of menopause on glucose and insulin metabolism, resulting in an increase in pancreatic insulin secretion and a decrease in insulin resistance, although other types of estrogen may not do this. Androgenic progestogens may oppose this potentially beneficial effect on insulin resistance. Central obesity is linked with many CHD risk factors, and HRT reverses the increased fat distribution that results from loss of ovarian function at the menopause. HRT may also improve the balance between coagulation and fibrinolysis, resulting in a reduction in arterial thrombosis. Finally, estradiol acts directly on the arterial wall, modifying both endothelium-dependent and calcium-dependent processes. These actions result in improved blood flow and reduced blood pressure and, importantly, have the potential to reduce myocardial ischaemia.

Negative effects of diuretic drugs on metabolic risk factors for coronary heart disease: Possible alternative drug therapies

The results of 8 major hypertension treatment trials, all using diuretics as first-line therapy, show a clear-cut reduction in stroke and congestive heart failure, but coronary heart disease (CHD) is not consistently benefited. It is unclear why CHD is not controlled, but diuretics can subtly upset metabolic risk factors for CHD, among which are lipid and glucose concentrations. Although these metabolic disturbances appear clinically unimpressive, risk table analysis reveals that they can offset or even reverse the benefits of reducing blood pressure. A link between glucose intolerance and increased serum lipid concentrations during diuretic-based therapy is suggested by multiple correlations between them. Replacement of diuretics as first-line therapy for mild and moderate hypertension should therefore be considered. Spironolactone seems to counter the adverse metabolic effects, but its effect on lipoproteins needs more study. A drug that does not disturb glucose and lipid metabolism would seem preferable. Thus prazosin is a promising candidate.