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Biomedical subjects

R H Bradford

Publications and source records attributed to R H Bradford.

At least 19 recordsLinked to original sources
PubMed1996

Efficacy and tolerability of lovastatin in 459 African-Americans with hypercholesterolemia.

A paucity of substantive data from clinical drug trials is available specifically evaluating the effects of therapy for hypercholesterolemia in African-Americans, even though a substantial number are candidates for medical advice and intervention for high blood cholesterol. The efficacy and safety of lovastatin in 459 African-Americans with hypercholesterolemia were studied in the Expanded Clinical Evaluation of Lovastatin study, a multicenter, double-blind, diet- and placebo-controlled trial. This trial involved 8,245 patients who were randomly assigned, regardless of race, to receive placebo or lovastatin at doses of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Among African-Americans, lovastatin produced sustained, dose-related (p <0.001) decreases in low-density lipoprotein cholesterol (20% to 38%), total cholesterol (14% to 28%), and triglycerides (8% to 15%). From 75% to 96% of African-Americans treated with lovastatin achieved the National Cholesterol Education Program goal of low-density lipoprotien cholesterol <160 mg/di, and from 33% to 71% achieved the goal <130 mg/di. The safety profile of lovastotin in African-Americans was generally favorable. A relatively high incidence of creatine kinase levels greater than the upper limit of normal was observed in African-Americans during the study, i.e., 63% in the placebo group and similar levels in lovastatin treatment groups. Lovastatin is highly effective and generally well tolerated as therapy for primary hypercholesterolemia in African-Americans.

Black or African American↗
PubMed1994

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up.

The Expanded Clinical Evaluation of Lovastatin study, a randomized, double-blind, placebo- and diet-controlled multicenter trial, evaluated the efficacy and tolerability of lovastatin over 48 weeks in 8,245 patients with moderately severe hypercholesterolemia. During year 1 of follow-up of the full cohort, lovastatin at 20 or 40 mg/day, or 20 or 40 mg twice daily, produced dose-dependent decreases in low-density lipoprotein (LDL) cholesterol (24% to 40%) and triglyceride levels (10% to 19%), and increases in high-density lipoprotein (HDL) cholesterol (6.6% to 9.5%). In all, 977 patients continued their original blinded treatment for an additional year. In year 2, the LDL cholesterol response to lovastatin was maintained, the triglyceride reductions were somewhat less, and the increases in HDL cholesterol were moderately greater than in year 1. Successive transaminase elevations > 3 times the upper limit of normal were observed in only 1 patient in year 2, yielding a cumulative 2-year incidence of from 0.1% (placebo or lovastatin 20 mg/day) to 1.9% (lovastatin 80 mg/day). Myopathy occurred in only 1 patient during year 2, and over the 2-year study was observed rarely and only at lovastatin dosages of 40 and 80 mg/day. This study indicates that lovastatin maintains its efficacy over long-term follow-up, particularly in effectively lowering LDL cholesterol, is generally well tolerated, and has a favorable safety profile.

Alanine Transaminase↗
PubMed1993

Efficacy and tolerability of lovastatin in 3390 women with moderate hypercholesterolemia.

OBJECTIVE: To evaluate the efficacy and safety of lovastatin in women with moderate hypercholesterolemia. DESIGN: The Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, in which participants were randomly assigned to receive placebo or lovastatin at doses of 20 or 40 mg once daily, or 20 or 40 mg twice daily for 48 weeks. SETTING: Ambulatory patients recruited by 362 participating centers throughout the United States. PATIENTS: Women (n = 3390) from the total cohort of 8245 volunteers. MEASUREMENTS: Plasma total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, and triglycerides; and laboratory and clinical evidence of adverse events monitored periodically throughout the study. RESULTS: Among women, lovastatin (20 to 80 mg/d) produced sustained (12- to 48-week), dose-related changes (P < 0.001): decreases in LDL cholesterol (24% to 40%) and triglycerides (9% to 18%), and increases in HDL cholesterol (6.7% to 8.6%). Depending on the dose, from 82% to 95% of lovastatin-treated women achieved the National Cholesterol Education Program goal of LDL cholesterol levels less than 4.14 mmol/L (160 mg/dL), and 40% to 87% achieved the goal of 3.36 mmol/L (130 mg/dL). Successive transaminase elevations greater than three times the upper limit of normal occurred in 0.1% of women and were dose dependent above the 20-mg dose. Myopathy, defined as muscle symptoms with creatine kinase elevations greater than 10 times the upper limit of normal, was rare and associated with the highest recommended daily dose of lovastatin (80 mg). Estrogen-replacement therapy appeared to have no effect on either the efficacy or safety profile of lovastatin. CONCLUSION: Lovastatin is highly effective and generally well tolerated as therapy for primary hypercholesterolemia in women.

Aged↗
PubMed1993

The diagnosis of diabetic retinopathy. Ophthalmoscopy versus fundus photography.

PURPOSE: To compare fundus photography with ophthalmoscopy in the detection of diabetic retinopathy. METHODS: Ophthalmoscopy and fundus photographs with a nonmydriatic camera, both performed through dilated pupils, were compared to diagnose retinopathy in a cohort of 410 Oklahoma Indians with noninsulin-dependent diabetes mellitus. A total of 795 eyes were examined using both methods. The mean age of participants was 60.3 years, with a mean duration of diabetes of 17.3 years. RESULTS: An overall agreement of 86.3% with a kappa statistic kappa of 0.74 was found between ophthalmoscopy and fundus photography with a nonmydriatic camera. For the diagnosis of proliferative diabetic retinopathy, kappa = 0.84 with an agreement of 98.1%. With a total of 61 cases of proliferative retinopathy diagnosed by either method in our study, ophthalmoscopy alone detected 88.5% and fundus photography, 78.7%. When compared on a lesion-by-lesion basis, agreement between the two diagnostic methods was highest for nonproliferative retinopathy, as well as fibrous proliferation. CONCLUSION: The fundus photography with a nonmydriatic camera, performed with mydriasis, is comparable to ophthalmoscopy for the detection of retinopathy. It may prove to be a suitable, cost-effective method for routine screening in diabetes clinics, provided ophthalmologic referral is ensured for those with a diagnosis of any form of retinopathy, questionable retinopathy, nondiabetic retinopathy, those with poor quality photographs, as well as those with acute changes in visual acuity.

Diabetes Mellitus, Type 2↗
PubMed1992

Double-blind comparison of bezafibrate versus placebo in male volunteers with hyperlipoproteinemia.

The efficacy and safety of bezafibrate were evaluated in 83 patients with type IIa, IIb, or IV hyperlipoproteinemia. Following a 12- to 14-week placebo period on a coronary-prudent diet (Period 1), patients were assigned randomly to receive either bezafibrate 600 mg/day or placebo, plus diet in a double-blind, 12-week treatment period (Period 2). The return of lipid and lipoprotein levels toward baseline was evaluated in a subsequent 8-week period on placebo plus diet (Period 3). In patients with type IIa hyperlipoproteinemia, bezafibrate significantly lowered total (14.6%, P less than 0.001) and LDL-cholesterol (16.4%, P less than 0.001) and total (29.9%, P less than 0.001) and VLDL-triglyceride (44.0%, P less than 0.001) and significantly increased HDL cholesterol (9.5%, P less than 0.001). In patients with type IIb, bezafibrate had a qualitatively similar effect to that seen in type IIa on each of these lipoproteins, but the sample size was too small for statistical evaluation. In patients with type IV, bezafibrate lowered total (48.3%, P less than 0.01) and VLDL-triglyceride (57.7%, P less than 0.001) and VLDL-cholesterol (56.8%, P less than 0.001) and increased HDL-cholesterol (16.6%, P less than 0.05). All values returned toward baseline during Period 3. Only two bezafibrate patients experienced adverse events that were considered definitely treatment related; one was dropped from the study because of elevations in SGOT and SGPT, 1.5- and 4-times the upper limit of normal, respectively. For other laboratory parameters, trends upward or downward were small and of doubtful clinical significance. Bezafibrate appears to be effective and safe for modifying lipid and lipoprotein levels in patients with types IIa, IIb and IV hyperlipoproteinemia.

Adolescent↗
PubMed1992

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. Effect of patient characteristics on lovastatin-induced changes in plasma concentrations of lipids and lipoproteins.

BACKGROUND: Lovastatin produces consistent dose-related reductions in plasma levels of low density lipoprotein (LDL) cholesterol along with variable decreases in triglycerides and increases in high density lipoprotein (HDL) cholesterol. Patient characteristics from the Expanded Clinical Evaluation of Lovastatin (EXCEL) study were examined to determine their association with the magnitude of lovastatin-induced changes in these lipids and lipoproteins. METHODS AND RESULTS: After a baseline period consisting of dietary therapy, 8,245 patients with moderate hypercholesterolemia were randomized to five groups that received 48 weeks of treatment with either placebo or daily doses of lovastatin ranging from 20 to 80 mg. By use of linear statistical models, 20 different patient characteristics were examined for modification of the dose-dependent responses observed. For LDL cholesterol, the following were associated with enhanced lowering (p less than 0.05; percent changes are placebo-corrected, adjusted mean changes from baseline for the 80-mg/day lovastatin group): full drug compliance (-41.9%) versus 80% compliance (-20.3%); an age of 65 (-43.4%) versus 45 years (-38.1%) for women; white race (-40.9%) versus black race (-38.0%); and 4.5-kg weight gain (-42.6%) versus 4.5-kg weight loss (-37.9%). Similar relations for enhanced triglyceride lowering were found with older age and weight gain. Patients with initially low HDL cholesterol (less than 0.91 mmol/l) and high triglycerides (greater than 2.26 mmol/l) had enhanced responses for these parameters: placebo-corrected percent changes at 80 mg/day were -27.4% for triglycerides and +12.3% for HDL cholesterol. CONCLUSIONS: Overall, patient characteristics had very little impact of clinical importance on the dose-dependent LDL cholesterol lowering found with lovastatin. In patients with initially high levels of triglycerides and low levels of HDL cholesterol, the elevation of HDL cholesterol produced by lovastatin appears to be enhanced.

Cholesterol, HDL↗
PubMed1992

Lovastatin and coadministered antihypertensive/cardiovascular agents.

Hypertension and hypercholesterolemia frequently coexist and may require concomitant drug treatments. The efficacy and safety profile of lovastatin given in the presence of antihypertensive medication was evaluated using patient subgroups identified in the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study. The EXCEL study examined 8,245 patients with moderate hypercholesterolemia randomly assigned either to a group treated with lovastatin (20-80 mg daily) or to a group given placebo for 48 weeks. After adjustment for patient characteristics, pairwise comparisons were made between patients taking no antihypertensive agents (n = 3,772) and those taking either calcium antagonists (n = 446), selective beta 1-adrenergic receptor blockers (n = 326), nonselective beta-adrenergic receptor blockers (n = 219), potassium-sparing diuretics (n = 187), thiazide diuretics (n = 126), or angiotensin converting enzyme inhibitors (n = 171). The placebo-corrected dose-dependent effect of lovastatin on the percent change from baseline in low-density lipoprotein cholesterol was not attenuated in any subgroup and was slightly enhanced in the calcium antagonist subgroup (-29% to -44%, p = 0.06) when compared with patients taking no antihypertensive agents (-24% to -40%); this difference, however, was only of borderline significance. Patterns of lovastatin-induced increase in high-density lipoprotein cholesterol and decrease in triglycerides were not consistently different among the subgroups. Examination of mean changes in serum transaminases, mean changes in creatine kinase, and the proportion of patients discontinuing therapy for clinical adverse experiences did not indicate the presence of an interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1992

Diabetic retinopathy in Oklahoma Indians with NIDDM. Incidence and risk factors.

OBJECTIVE: To determine the incidence rates and risk factors for development of diabetic retinopathy in Oklahoma Indians. RESEARCH DESIGN AND METHODS: Cohort follow-up study with baseline examination between 1972 and 1980 and follow-up examination between 1987 and 1991. Mean +/- SD follow-up time was 12.8 +/- 1.7 yr. Eleven Indian Health Service facilities (clinics and hospitals) in Oklahoma participated in the study. Study participants were a quasirandom sample of 1012 American Indians (379 men, 633 women) in Oklahoma with NIDDM, 927 of whom received a detailed eye examination at baseline. The mean age of participants was 52 yr with a duration of diabetes of 6.9 yr at baseline. The average quantum of Indian blood was 92% (77% full blood). At follow-up, 515 (55.6%) were alive, 408 (44.0%) were deceased, and 4 (0.4%) could not be traced. Of the living participants, 380 (73.8%) underwent an ophthalmoscopic examination. RESULTS: The incidence of retinopathy among the participants who were free of disease at baseline and who survived the follow-up interval was 72.3%. By multivariate analysis, significant independent predictors of retinopathy recorded at baseline were FPG level, therapeutic regimen, systolic blood pressure, and duration of diabetes. FPG levels > or = 11.1 mM (200 mg/dl) increased the risk of retinopathy 1.7 times that for levels < 7.8 mM (140 mg/dl). Insulin use was associated with a 20% greater incidence. Hypertension was a particularly significant risk factor for those with lower FPG levels. CONCLUSIONS: Given that NIDDM is reaching epidemic proportions in Oklahoma Indians and that most may be afflicted with retinopathy, frequent ophthalmological examinations are clearly indicated for this high-risk population. The role of intervention, namely glycemic and hypertensive control, deserves further study.

Blood Glucose↗
PubMed1991

Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia.

In the multicenter, double-blind EXCEL (Expanded Clinical Evaluation of Lovastatin) study the efficacy of lovastatin in modifying plasma lipids and lipoproteins in 8,245 participants with moderate primary hypercholesterolemia was evaluated. Patients were randomly assigned to 48 weeks of treatment with diet and placebo or diet and lovastatin 20 or 40 mg once a day, or 20 or 40 mg twice a day. At all of these dosages, lovastatin produced substantial dose-dependent reductions in low-density-lipoprotein (LDL)-cholesterol levels, averaging 24% (20 mg/day) to 40% (80 mg/day). The magnitude of the effect of this lipoprotein was further reflected by the percentage of patients who achieved National Cholesterol Education Program (NCEP) goals. In the absence of coronary artery disease (CAD) or two other CAD risk factors, the LDL-cholesterol goal of 4.14 mmol/L (160 mg/dL) was attained by 22% of patients in the placebo group and between 81% (20 mg/day) and 96% (80 mg/day) of those treated with lovastatin. For those with CAD or at least two other CAD risk factors, the LDL-cholesterol goal of 3.36 mmol/L (130 mg/dL) was attained by 4% of placebo patients and between 38% (20 mg/day) and 83% (80 mg/day) of those treated with lovastatin. Lovastatin also increased high-density-lipoprotein cholesterol (7-10%) and decreased triglycerides (10-19%) in a dose-dependent manner. Thus, when used as an adjunct to a prudent diet, lovastatin produces favorable changes in the entire lipoprotein profile and is a highly effective agent for managing patients with primary hypercholesterolemia.

Cholesterol, HDL↗
PubMed1991

Expanded clinical evaluation of lovastatin (EXCEL) study results: IV. Additional perspectives on the tolerability of lovastatin.

This randomized, double-blind, multicenter, diet-and-placebo-controlled study was designed to clarify the dose-response relationship of lovastatin therapy to lipid-modifying efficacy and drug-related adverse events. Exclusion criteria were minimized so that study patients were representative of the majority of patients with moderate hypercholesterolemia seen in medical practice. After 6 weeks on the American Heart Association Step 1 Diet, a total of 8,245 patients were randomly assigned to 48 weeks of treatment with diet and placebo or lovastatin at dosages of 20 or 40 mg once a day or 20 or 40 mg twice a day. All adverse events were monitored, with particular attention to evaluation of liver and muscle. Liver transaminase elevations suggestive of possible hepatotoxicity, defined as successive elevations in either aspartate transaminase or alanine aminotransferase greater than 3 times the upper limit of normal, occurred in equal numbers of placebo and lovastatin 20 mg/day treated patients (0.1%). The frequencies were higher in lovastatin 40 mg/day and 80 mg/day patient groups (0.9 and 1.5%, respectively). No patient was diagnosed as having clinically symptomatic hepatic dysfunction. Creatinine kinase (CK) elevations above the upper limit of normal occurred frequently in placebo- (29%), as well as lovastatin-treated patients (29-35%), and muscle symptoms were reported with similar frequency in all groups (7-9%). The combination of muscle symptoms with marked CK elevations (greater than 10 times the upper limit of normal) was seen in only five patients: one in a 40 mg/day dose group and four in the 80 mg/day dose group. No patient developed rhabdomyolysis. The incidence of clinical and laboratory adverse events requiring discontinuation was 6% for the placebo group and from 7% (20 mg/day) to 9% (80 mg/day) for lovastatin treatment groups. No new types of adverse experiences related to lovastatin treatment were reported. Lovastatin, as an adjunct to diet for the reduction of elevated LDL cholesterol, was generally very well tolerated.

Alanine Transaminase↗
PubMed1991

Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia.

In the Expanded Clinical Evaluation of Lovastatin (EXCEL) Study, a multicenter, double-blind, diet- and placebo-controlled trial, we evaluated the efficacy and safety of lovastatin in 8245 patients with moderate hypercholesterolemia. Patients were randomly assigned to receive placebo or lovastatin at a dosage of 20 mg once daily, 40 mg once daily, 20 mg twice daily, or 40 mg twice daily for 48 weeks. Lovastatin produced sustained, dose-related (P less than .001) changes as follows (for dosages of 20 to 80 mg/d): decreased low-density lipoprotein-cholesterol level (24% to 40%), increased high-density lipoprotein-cholesterol level (6.6% to 9.5%), decreased total cholesterol level (17% to 29%), and decreased triglyceride level (10% to 19%). The National Cholesterol Education Program's low-density lipoprotein-cholesterol level goal of less than 4.14 mmol/L (160 mg/dL) was achieved by 80% to 96% of patients, while the less than 3.36 mmol/L (130 mg/dL) goal was achieved by 38% to 83% of patients. The difference between lovastatin and placebo in the incidence of clinical adverse experiences requiring discontinuation was small, ranging from 1.2% at 20 mg twice daily to 1.9% at 80 mg/d. Successive transaminase level elevations greater than three times the upper limit of normal were observed in 0.1% of patients receiving placebo and 20 mg/d of lovastatin, increasing to 0.9% in those receiving 40 mg/d and 1.5% in those receiving 80 mg/d of lovastatin (P less than .001 for trend). Myopathy, defined as muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal, was found in only one patient (0.1%) receiving 40 mg once daily and four patients (0.2%) receiving 80 mg/d of lovastatin. Thus, lovastatin, when added after an adequate trial of a prudent diet, is a highly effective and generally well-tolerated treatment for patients with moderate hypercholesterolemia.

Adult↗
PubMed1991

The use of the Penlon Nuffield 200 in a monoplace hyperbaric oxygen chamber. An evaluation of its use and a clinical report in two patients requiring ventilation for carbon monoxide poisoning.

We modified a Penlon Nuffield 200 for use in a monoplace hyperbaric oxygen chamber by feeding back the chamber pressure to the reducing valve of the Nuffield 200. This provides a compensating mechanism, allowing the ventilator to deliver adequate tidal volumes at pressures of up to 3 atmospheres. We report the laboratory testing of the ventilator and our experience of ventilating two patients with carbon monoxide poisoning. Although compensation is not complete the modification is adequate for short-term clinical use in patients in whom the airway is compromised but who need hyperbaric oxygen therapy.

Adult↗
PubMed1990

Expanded clinical evaluation of lovastatin (EXCEL) study: design and patient characteristics of a double-blind, placebo-controlled study in patients with moderate hypercholesterolemia.

The randomized, double-blind, placebo-controlled trial described in this report was undertaken to clarify the dose-response relation of lovastatin therapy to lipid-modifying efficacy (lipid/lipoprotein modification) and drug-related adverse events in a population with moderately elevated fasting plasma total cholesterol (240 to 300 mg/dl) and low-density lipoprotein cholesterol (greater than or equal to 160 mg/dl). Men or women (postmenopausal or surgically sterile), aged 18 to 70 years, were entered into the trial with minimal exclusion criteria. After 4 to 6 weeks of an American Heart Association phase I diet or a more stringent diet, 8,245 patients from 362 sites were randomized to 1 of 5 parallel diet and drug treatment groups: placebo (n = 1,663) or lovastatin, 20 mg (n = 1,642) and 40 mg (n = 1,645) with the evening meal, and 20 mg (n = 1,646) or 40 mg twice daily (n = 1,649). The regimen of diet and lovastatin (or placebo) was followed for 48 weeks. The 5 treatment groups were similar at baseline. The total cohort had the following characteristics: 59% were men (mean age 56 years); 92% were white; 59% had completed at least 1 year of education beyond high school; 57% had a history of cardiovascular and associated disease; 40% had a history of hypertension; and 29% had coronary artery disease. Health habits were similar among groups, with 18% of patients reporting cigarette smoking, 14% reporting that they consume greater than 1 alcoholic beverage daily and 67% reporting no strenous exercise. Mean lipid/lipoprotein levels were also similar among groups, with the following average levels: total cholesterol (258 mg/dl), low-density lipoprotein cholesterol (180 mg/dl), high-density lipoprotein cholesterol (45 mg/dl) and triglycerides (median = 155 mg/dl). The large size of this trial, its placebo-controlled, double-blind design and the similarity of treatment groups at baseline should allow clear documentation of the long-term effects of lovastatin treatment and generalization of the results to a substantial portion of patients who may be candidates for lipid-modifying therapy.

Adult↗
PubMed1990

Blood cholesterol screening in several environments using a portable, dry-chemistry analyzer and fingerstick blood samples. Lipid Research Clinics Cholesterol Screening Study Group.

A multicenter study of blood cholesterol screening was performed in several typical environments, such as community sites (shopping malls and a supermarket), health care sites, work sites, a blood bank and a school. Cholesterol was measured with a portable, dry-chemistry analyzer using capillary blood obtained by fingerstick. Data are reported from a total of 13,824 participants, spanning the entire age spectrum. Overall, 25% of screened subjects had blood cholesterol levels above the age-specific cutpoints used in the current study. Although in the aggregate this screening experience very closely approximates the expected level of referrals, the proportion of referred screened subjects differed significantly among the 5 types of screening environments and by gender. Follow-up telephone interviews indicated that 53% of referrals had initiated a physician contact. More than 75% of those who had seen a physician reported that the diagnosis of hypercholesterolemia had been confirmed, and almost 72% had been prescribed a diet. A large proportion of referred screened subjects reported having modified their diet, particularly when recommended to do so by a physician. This study has yielded encouraging evidence that physicians gave referred screened subjects appropriate initial advice for managing hypercholesterolemia. The new technology for blood cholesterol measurement evaluated in the current study has proven to be a feasible and reliable means for measuring blood cholesterol in typical screening settings.

Adult↗
PubMed1989

Lowering blood cholesterol to reduce coronary heart disease risk.

Key recent findings provide definitive evidence that lowering blood cholesterol in humans reduces coronary heart disease risk. These research advances serve as the basis for national guidelines concerning the medical and public health implications of lowering blood cholesterol to prevent heart disease.

Cholesterol↗
PubMed1989

Screening for high blood cholesterol.

The detection and treatment of high blood cholesterol will require a sizeable screening effort. To a large extent, the screening can be accomplished through routine medical care, but screenings conducted at public or community sites also offer promise. The NCEP will ultimately recommend whether or not public screening should supplement that performed in the physician's office. In the meantime, the National Heart, Lung and Blood Institute has issued screening guidelines that address critical issues including reliability of cholesterol measurement, compliance to the education and referral advice given at screening, and physician readiness to evaluate and treat those referred. Findings from the Model System for High Blood Cholesterol Screening and other research projects provided a basis for such recommendations. It is hoped that these guidelines will ensure high quality public screening.

Cholesterol↗