Serum cholesterol during treatment of hypertension with diuretic drugs.

Twenty-three men had an increase in serum levels of total cholesterol and triglycerides after starting a diet to lower their serum cholesterol. They had simultaneously started therapy with, or increased the dosage of, chlorthalidone or hydrochlorothiazide for the treatment of hypertension. To evaluate a possible role of the diuretics in the increase in serum lipid concentrations, 11 of the men were randomly allocated to spironolactone therapy for two to four months. After receiving spironolactone, cholesterol levels decreased by 24 mg/dL, whereas cholesterol levels decreased by only 3 mg/dL in the 12 men still receiving chlorthalidone (P less than .05). The triglyceride level decreased by 58 mg/dL after the change to spironolactone therapy, whereas it decreased by 10 mg/dL during continued chlorthalidone treatment (P less than .05). When the 11 men again received chlorthalidone, their cholesterol levels increased 16 mg/dL, whereas cholesterol levels decreased by 11 mg/dL in men receiving uninterrupted chlorthalidone treatment (P less than .01). These observations suggest that spironolactone may be a preferable alternative to thiazide-type agents as first-line therapy for hypertension because of the more favorable influence on serum lipid concentrations.

Elevation of serum lipid levels during diuretic therapy of hypertension.

In a study attempting to improve coronary risk status, serum cholesterol and triglyceride levels were measured before and during treatment of 74 patients with mild primary hypertension. In 35 patients there was a satisfactory reduction in elevated blood pressure levels with diet therapy alone. In the remaining 39 patients a diuretic drug was required in addition to the diet. Diet therapy alone was followed by a decrease of 11 mg/100 ml in mean serum cholesterol (p less than 0.01 versus pretreatment value) and no change in serum triglyceride. The sue of diuretics was accompanied by an average increase of 11 mg/100 ml in serum cholesterol and of 34 mg/100 ml in serum triglyceride (p less than 0.01 versus pretreatment level for both). In a subgroup of 21 patients with greatest elevations in lipid levels during the administration of diuretics, little improvement in coronary risk status occurred because the increase in serum cholesterol balanced the decrease in systolic blood pressure, according to Framingham risk tables. If the level of serum lipids is a factor in the pathogenesis of coronary atherosclerosis then the observed effect of diuretic drugs to elevate serum cholesterol and triglyceride levels may explain, in part, the continuing high rate of occurrence of myocardial infarction during the treatment of hypertension.

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.

A comparison of blood lipid and blood pressure responses during the treatment of systemic hypertension with indapamide and with thiazides.

Thiazide diuretics in high dosage adversely affect the lipid profile. The non-thiazide indoline, indapamide, appears to be free of this effect, but it is unclear whether this apparent metabolic advantage of indapamide is superior to thiazides used in low dose. Since there are no large direct comparative studies to test this distinction, I surveyed the literature and pooled the findings of all published reports giving data on lipid and blood pressure effects of thiazides in various doses and of both indapamide, 2.5 mg daily, used as monotherapy of hypertension. I found 31 reports of thiazides; 12 of them examined low-dose regimens, i.e., < or = 25 mg/day of hydrochlorothiazide or its equivalent in other thiazides. Larger doses of thiazides were tested in 19 studies (median daily dose of 50 mg, maximum dose of 112.5 mg). There were 430 subjects in the low-dose studies and 559 subjects in the high-dose regimens. There were 13 studies of indapamide, comprising 558 subjects. Regarding lipids, total cholesterol increased from baseline by 1.4% on indapamide, 3.8% on low-dose thiazides, and 6.3% on high-dose thiazides, The change from baseline was significantly greater for high-dose thiazides than for indapamide (p<0.01). Changes in high-density lipoprotein cholesterol did not differ among groups. The change in triglycerides differed among regimens, -0.5%, 10.8%, and 19.5% for indapamide, low-dose thiazides, and high-dose thiazides, respectively (p<0.01). Systolic blood pressure (SBP) decreased by 13 and 18 mm Hg on low-dose and high-dose thiazides, respectively (p<0.05 between doses). Indapamide lowered SBP by 16 mm Hg, not different from either thiazide dose. Diastolic blood pressure did not differ among groups. From these noncomparative studies, I conclude that (1) indapamide has no adverse lipid effect and lowers blood pressure equally to thiazides; (2) thiazide effects on lipids and SBP are dose-dependent; and (3) thiazides adversely affect the lipid profile even in low dose.

Effectiveness of doxazosin in systemic hypertension.

Most alpha-receptor blocking drugs require divided daily administration because of a short plasma half-life. This multicenter study examined the effectiveness and safety of once-daily administration with doxazosin, a quinazoline analog alpha 1-receptor blocking drug with a plasma half-life of 19 hours. Patients with diastolic blood pressure (BP) of 90 to 115 mm Hg entered 4 weeks of single-blind placebo therapy and then were randomized to double-blind treatment with doxazosin (63 patients) or placebo (67 patients). After 10 weeks of titration, standing arterial BP was lowered by 14/11 mm Hg with doxazosin and by 0.5/0.9 mm Hg with placebo (p less than 0.001). Measured hourly for 12 hours after the dose, all standing and supine arterial BP values were significantly lower in the doxazosin group at each hour. Pulse rate increased slightly in both groups int he double-blind phase, but the increase with doxazosin never significantly exceeded that of placebo. Dizziness was the most common complaint with doxazosin, but syncope did not occur. Side effects were mild and transient and did not necessitate withdrawing any participants from the study. Body weight increased by 1.5 kg in the doxazosin group and decreased by 0.2 kg in the placebo group (p less than 0.01). Safe and effective in once-daily administration, doxazosin is suitable for initial therapy in mild and moderate hypertension.

The effects of antihypertensive drugs on serum lipids and lipoproteins, I. Diuretics.

Potassium-losing diuretic drugs, when used in the treatment of hypertension, cause unfavourable short term alterations in blood lipid and lipoprotein concentrations. The disturbance is characterised by increases in total cholesterol of 4 to 13%, in low density lipoprotein (LDL) cholesterol of 7 to 29%, in very-low density lipoprotein (VLDL) cholesterol of 7 to 56%, and in total triglyceride of 14 to 37%. The disturbance is variable among patients and over time in individual patients; it is absent in some. In long term treatment the data are fragmentary, but total cholesterol and triglycerides usually return to baseline values or below. The variability of the lipid response to diuretics has several consequences: firstly, it necessitates a sizeable study population (minimum of 30 patients) in order to document convincingly its presence or absence; secondly, lipoprotein fractions must be examined to define the pattern of the disturbance; and thirdly, the subsidence of the diuretic-induced lipid effects in long term treatment may be more apparent than real because even larger decreases have been noted in untreated groups in the few studies that wisely included these important controls for comparison. While the cause of the lipid-lipoprotein aberration is unclear, existing data suggest that certain attributes of the study population influence the response, i.e. age, habitual diet, hormonal milieu (gender), baseline cholesterol concentrations, and induced glucose intolerance. The apparent absence of lipid alterations with indapamide needs to be substantiated and compared with low doses of a standard thiazide-type drug. The lipid-lipoprotein effects of diuretics seem inconsequentially small, but they may contribute to the disappointing failure of diuretic-based regimens to lower the incidence of coronary heart disease in hypertensive patients. Nevertheless, diuretic-based treatment remains the only therapeutic regimen of proven benefit to congestive heart failure in patients with hypertension, and it is superior to beta-blockade in preventing stroke. Hence, alternative antihypertensive drug regimens must be compared prospectively with diuretics in order to verify any theoretic superiority.

The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Non-diuretic drugs.

This review examines the effects of various antihypertensive drugs on blood lipids, lipoproteins, and apolipoproteins. A large number of studies have documented the elevation of total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, and very-low density lipoprotein (VLDL) cholesterol with many thiazide-type diuretic drugs, albeit mainly in short term studies. When added to thiazide diuretics, both beta 1-selective and non-selective beta-blocking drugs elevate total triglycerides and VLDL triglycerides, lower high density lipoprotein (HDL) cholesterol and raise the ratio of total cholesterol to HDL cholesterol ratio. Most non-selective beta-blockers have similar effects when used as monotherapy, but the beta 1-selective agents appear not to affect HDL cholesterol in monotherapy. Prazosin appears free of adverse lipid effects and has improved lipid-lipoprotein concentrations in many studies. Preliminary data on several other drugs also suggest a favourable lipid profile and additional study is warranted - among these are guanabenz, clonidine, pindolol, labetalol, indapamide, and guanfacine. Elevations in serum triglycerides are often ignored on various counts, but triglycerides have been found to be a strong risk factor in European studies and in women over the age of 50 years in the Framingham study. Despite the unfavourable short term effects of diuretics, the theoretical risk of the lipid-lipoprotein changes remains unclear because HDL cholesterol and the total cholesterol to HDL cholesterol ratio are often unchanged. For this and other reasons, a long term trial comparing thiazide-type diuretics with drugs with the most favourable lipid-lipoprotein profile is needed. Until this is accomplished, in most settings diuretic-based regimens are still preferred initially since they are of proven, if limited, efficacy against the cardiovascular complications of hypertension.

Antihypertensive drugs and lipid profiles.

The large clinical trials of the treatment of hypertension, in which diuretics were used as initial drug therapy, have demonstrated a major reduction in stroke but little benefit in the incidence of coronary heart disease. The limited effect of treatment on coronary disease is surprising given the strong risk factor relationship to pre-existing hypertension. This may mean that the risk factor relationship is not a causal one. Alternatively, the drug therapy may have subtle toxicity that in the long term offsets the benefit of lowering blood pressure. This review explores the latter possibility by reviewing the evidence that the antihypertensive drugs used preferentially heretofore have adverse effects on the lipid profile. Diuretics increase triglycerides (average of 30%), total cholesterol (average of 6-8%), and LDL or VLDL cholesterol. beta-1 selective and nonselective beta-blockers increase triglycerides (average of 30%) and lower HDL cholesterol (average of 5-15%). Whereas the adverse modifications of the lipid profile appear small and inconsequential, the increase in total cholesterol during diuretic therapy is of the same magnitude as observed in the Lipid Research Clinic trial (although opposite in direction) that significantly affected coronary events. The persistence of the lipid changes during long-term treatment is unresolved due to fragmentary and poorly controlled observations. Nevertheless, considerable data suggest that it continues during extended therapy. Selective alpha-1 adrenoceptor blocking drugs and perhaps calcium antagonists and beta-blockers with intrinsic sympathomimetic activity have a favorable influence on the lipid profile.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus.

Severe short-term sodium restriction or extreme sodium loading may alter glucose tolerance and insulin resistance in patients with hypertension, but it is unclear whether variations in sodium intake within the clinically observed range affect glucose tolerance. To examine this issue, 21 patients with primary hypertension with average sodium excretion of 116+/-55 mEq/day were randomized to consecutive 4-week periods of placebo therapy and sodium chloride supplementation 2 g four times a day in a single-blind crossover study design. A 75-g oral glucose tolerance test (GTT) with simultaneous insulin levels was performed at the end of each intervention period. For the group as a whole, urinary sodium excretion increased on sodium chloride to 267+/-118 mEq/day versus control (placebo) phase of 135+/-53 mEq/day, P < .001. Total glycemic response in the oral GTT (area under the glucose curve) was 8.0% lower during sodium supplementation, P < .001. Secondary analysis revealed that the effect of sodium was noteworthy in 1) type 2 diabetic subjects (n = 8), 2) sodium-sensitive subjects (n = 10), and 3) nondiabetic subjects receiving antihypertensive drug treatment (n = 6). The total insulinemic response to oral GTT was also lowered by sodium loading among diabetic subjects. Thus, an abundant sodium intake may improve glucose tolerance and insulin resistance, especially in diabetic, salt-sensitive, and or medicated essential hypertensive subjects.

Alpha-1 adrenoceptor blockade with doxazosin in hypertension: effects on blood pressure and lipoproteins.

The effects of doxazosin, a long-acting alpha-1 adrenoreceptor blocking drug, were observed upon blood pressure and serum lipoproteins. Thirty patients with supine diastolic blood pressure between 90 and 114 mm Hg during single-blind placebo therapy were randomized to double-blind treatment with either doxazosin or further placebo in a parallel-design protocol. Starting at one mg, dosage was doubled every 2 weeks during a 10-week treatment period to a maximum dose of 16 mg once daily. Blood was sampled in the fasting state before and during double-blind therapy for measurement of total cholesterol and triglycerides, cholesterol in the lipoprotein fractions, and apolipoproteins A and B. At the end of 10 weeks of titration, systolic and diastolic blood pressure were each reduced by 14 mm Hg in the standing position when measured 24 hours following the previous dose. Supine pressure was lowered by 6 mm Hg systolic and by 5 mm Hg diastolic at the same time point. Measured hourly for 12 hours following the ingestion of doxazosin, blood pressure was lowered maximally at 4-5 hours when an additional decline of 14/6 mm Hg (systolic/diastolic) was observed in the standing position and 13/6 in the supine posture. Postural dizziness, the most frequent symptomatic complaint, was reported in 4 patients during doxazosin treatment. After brief interruption of treatment in one and dosage adjustment in another, titration was continued in all four and no patient was withdrawn because of side effects. Concerning lipoproteins, the ratio of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol both improved during treatment with doxazosin.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension.

In the final analysis of this study at Week 26, 26% of the patients randomized to receive amlodipine attained blood pressure control with amlodipine alone compared with 33% of the patients allocated to hydrochlorothiazide (HCTZ). Neither amlodipine nor HCTZ produced clinically significant changes in pulse rate or in the electrocardiogram. Amlodipine treatment did not appear to produce clinically significant changes in blood lipids; HCTZ, however, produced an increase in total plasma cholesterol (delta 22.9 +/- 8.6 mg/dl). The incidence of side effects and the rate of patient withdrawal in the amlodipine and HCTZ groups were comparable. As expected, HCTZ therapy caused well-recognized biochemical alterations in cholesterol and potassium levels, whereas amlodipine was metabolically neutral.

National Beef Quality Audit-1995: survey of producer-related defects and carcass quality and quantity attributes.

The National Beef Quality Audit-1995 was conducted to evaluate the progress of the beef industry since the time of the National Beef Quality Audit-1991 in improving quality and consistency of beef. Nine plants were assigned for auditing to Colorado State University, Oklahoma State University, and Texas A&M University. Personnel from each institution visited three of their nine plants twice, once in the spring/summer and once in the fall/winter. Data were collected on 50% of each lot on the slaughter floor and 10% in the cooler during a single day's production (one or two shifts, as appropriate). Of the cattle audited on the slaughter floor, 47.7% had no brands, 3.0% had a shoulder brand, 16.8% had a side brand, 38.7% had a butt brand, and 6.2% had brands in multiple locations. Data revealed that 51.6% of the carcasses had no bruises, 30.9% had one bruise, 12.8% had two bruises, 3.7% had three bruises, .9% had four bruises, and .1% had more than four bruises. In addition, 7.2% of the bruises evaluated were located on the round, 41.1% were on the loin, 20.8% on the rib, and 30.8% on the chuck. Livers, lungs, tripe, heads, tongues, and whole carcasses were condemned at rates of 22.2, 5.0, 11.0, .9, 3.8, and .1%, respectively. Mean USDA yield grade and quality grade traits were as follows: USDA yield grade, 2.8; carcass weight, 338.4 kg; adjusted fat thickness, 1.2 cm; longissimus muscle area, 81.9 cm2; kidney, pelvic, and heart fat, 2.1%; USDA quality grade, High Select; overall maturity, A60; and marbling score, Small-minus.

Palatability of beef steaks marinated with solutions of calcium chloride, phosphate, and (or) beef-flavoring.

This study evaluated the efficacy of marination for increasing consumer acceptability of beef. Top-sirloin steaks from 28 USDA select steers were randomly assigned to one of six marination treatments: control (CT), 150 mM calcium chloride (CA), 10% solution of beef-flavoring/seasoning mixture (FL), CA and FL (CF), 2.5% sodium phosphate and FL (PF), and tap water (TW). Steaks were marinated in vacuum pouches, aged for 7 days, cooked to 70°C and evaluated by a trained sensory panel. Marination with CA did not affect tenderness ratings, but increased (P<0.05) bitter and metallic flavors compared to CT or TW treatments. Use of FL, alone or in conjunction with CA or sodium phosphate, increased (P<0.05) tenderness and juiciness ratings and reduced (P<0.05) bitterness and metallic flavors compared to CT, CA and TW marinades. Marination of beef, in vacuum pouches, is an effective method for increasing consumer acceptability and value beef.

The influence of non-beta-blocking drugs on the lipid profile: are diuretics outclassed as initial therapy for hypertension?

Diuretic drugs, when used in the treatment of hypertension, raise the blood concentrations of total cholesterol and low-density or very low-density lipoprotein cholesterol. Triglycerides often increase as well. Thiazide, phthalimidine, loop, potassium-sparing, and methylindoline drugs produce a similar effect. Only indapamide, a methylindoline agent with vasodilator activity, has been free of adverse lipid effects. It remains unclear whether it is the low dose of indapamide or some other quality that frees it of this effect. In long-term diuretic therapy, total cholesterol returns to, or below, baseline values, suggesting that the lipid elevations are transitory. However, in studies with adequate control groups, total cholesterol declines below baseline valves in control subjects such that an adverse differential in lipid values persists in long-term treatment. Selective alpha-1-adrenoceptor-blocking drugs cause no change or favorable alterations in lipid concentrations in short-term and long-term (1 year) treatment. Among all antihypertensive drugs, this class of agents, and especially prazosin, has produced the most consistently salutary lipid and metabolic effects. Although less well examined, guanabenz, clonidine, guanfacine, and diltiazem have been associated with favorable lipid changes. Captopril and nifedipine have caused no change in lipid-lipoprotein values in limited investigations. These agents are preferable to diuretics and certain beta blockers with respect to short-term effects on lipids and lipoproteins. Their ultimate superiority as monotherapy depends on whether they lower blood pressure equally well. Lowering of the probability of coronary heart disease in hypertensive patients depends as much on blood pressure control as on lipid effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperlipidemia in hypertension: causes and prevention.

Hyperlipidemia is prevalent in hypertension, but the cause of this association is unknown. Treatment of hypertension with thiazide diuretics accentuates the hyperlipidemia, perhaps by causing potassium or sodium depletion. To assess the role of hypokalemia in thiazide hyperlipidemia, I measured lipid concentrations while using a spironolactone-thiazide regimen to prevent potassium wastage during the treatment of hypertension. Blood pressure decreased substantially, but hyperlipidemia occurred despite the maintenance of normal serum potassium. To test a role of sodium balance, I measured lipid levels during periods of sodium feeding and placebo therapy. Cholesterol levels decreased during sodium administration. Carrying this information to therapy, I participated in a multicenter comparison of enalapril and indapamide therapy in resistant hypertension. Both regimens caused minor metabolic effects, but indapamide provided superior antihypertensive potency. This evidence suggests that sodium feeding improves lipid metabolism, but sodium diuresis enhances an antihypertensive effect. Low-dose therapy combining a diuretic, such as indapamide, with a nondiuretic agent promises to improve metabolic tolerance and maximize hypertension control. This strategy optimally lowers overall cardiovascular risk.

Coronary heart disease and the treatment of hypertension: impact of diuretics on serum lipids and glucose.

In summary, diuretic-based antihypertensive therapy causes glucose intolerance and raises glycohemoglobin concentrations as well as blood cholesterol and triglycerides. Various indices of glucose intolerance correlate with alterations in lipid concentrations. The correlations suggest that these metabolic disturbances are linked or have a common mechanism. When the three CHD risk factors of glucose, cholesterol and SBP are considered together, the net change during diuretic-based treatment may not be uniformly favorable. Other antihypertensive regimens might produce a move salubrious effect on the risk factors. Once identified, such regimens will need to be tested against diuretic regimens to ascertain whether the theoretical advantage suggested by risk factor analysis translates into a reduction in real-life coronary events.