The primary objective of this 6-week, parallel-group, open-label, randomized, multicenter trial was to compare rosuvastatin with atorvastatin, pravastatin, and simvastatin across dose ranges for reduction of low-density lipoprotein (LDL) cholesterol. Secondary objectives included comparing rosuvastatin with comparators for other lipid modifications and achievement of National Cholesterol Education Program Adult Treatment Panel III and Joint European Task Force LDL cholesterol goals. After a dietary lead-in period, 2,431 adults with hypercholesterolemia (LDL cholesterol ≥160 and <250 mg/dl; triglycerides <400 mg/dl) were randomized to treatment with rosuvastatin 10, 20, 40, or 80 mg; atorvastatin 10, 20, 40, or 80 mg; simvastatin 10, 20, 40, or 80 mg; or pravastatin 10, 20, or 40 mg. At 6 weeks, across-dose analyses showed that rosuvastatin 10 to 80 mg reduced LDL cholesterol by a mean of 8.2% more than atorvastatin 10 to 80 mg, 26% more than pravastatin 10 to 40 mg, and 12% to 18% more than simvastatin 10 to 80 mg (all p <0.001). Mean percent changes in high-density lipoprotein cholesterol in the rosuvastatin groups were +7.7% to +9.6% compared with +2.1% to +6.8% in all other groups. Across dose ranges, rosuvastatin reduced total cholesterol significantly more (p <0.001) than all comparators and triglycerides significantly more (p <0.001) than simvastatin and pravastatin. Adult Treatment Panel III LDL cholesterol goals were achieved by 82% to 89% of patients treated with rosuvastatin 10 to 40 mg compared with 69% to 85% of patients treated with atorvastatin 10 to 80 mg; the European LDL cholesterol goal of <3.0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments.

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* trial)

background Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. methods Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (±SD) follow-up of 7.3±0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. results At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors.

/pdf/vascular-risk-factors-and-diabetic-neuropathy-booz13gf7m.pdf

Vascular risk factors and diabetic neuropathy

ContextThe Women's Health Initiative (WHI) trial of estrogen plus progestin
was stopped early because of adverse effects, including an increased risk
of stroke in the estrogen plus progestin group.ObjectiveTo assess the effect of estrogen plus progestin on ischemic and hemorrhagic
stroke and in subgroups, and to determine whether the effect of estrogen plus
progestin was modified by baseline levels of blood biomarkers.DesignMulticenter double-blind, placebo-controlled, randomized clinical trial
involving 16 608 women aged 50 through 79 years with an average follow-up
of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis,
and lipid levels were measured in the first 140 centrally confirmed stroke
cases and 513 controls.InterventionsParticipants received 0.625 mg/d of conjugated equine estrogen plus
2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).Main Outcome MeasuresOverall strokes and stroke subtype and severity were centrally adjudicated
by stroke neurologists.ResultsOne hundred fifty-one patients (1.8%) in the estrogen plus progestin
and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes
were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat
hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence
interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50
(95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90)
and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the
HRs indicate that excess risk of all stroke was apparent in all age groups,
in all categories of baseline stroke risk, and in women with and without hypertension,
prior history of cardiovascular disease, use of hormones, statins, or aspirin.
Other risk factors for stroke, including smoking, blood pressure, diabetes,
lower use of vitamin C supplements, blood-based biomarkers of inflammation,
higher white blood cell count, and higher hematocrit levels did not modify
the effect of estrogen plus progestin on stroke risk.ConclusionsEstrogen plus progestin increases the risk of ischemic stroke in generally
healthy postmenopausal women. Excess risk for all strokes attributed to estrogen
plus progestin appeared to be present in all subgroups of women examined.

https://jamanetwork.com/journals/jama/articlepdf/196626/joc30333.pdf

Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial.

ContextPopular diets, particularly those low in carbohydrates, have challenged current recommendations advising a low-fat, high-carbohydrate diet for weight loss. Potential benefits and risks have not been tested adequately.ObjectiveTo compare 4 weight-loss diets representing a spectrum of low to high carbohydrate intake for effects on weight loss and related metabolic variables.Design, Setting, and ParticipantsTwelve-month randomized trial conducted in the United States from February 2003 to October 2005 among 311 free-living, overweight/obese (body mass index, 27-40) nondiabetic, premenopausal women.InterventionParticipants were randomly assigned to follow the Atkins (n = 77), Zone (n = 79), LEARN (n = 79), or Ornish (n = 76) diets and received weekly instruction for 2 months, then an additional 10-month follow-up.Main Outcome MeasuresWeight loss at 12 months was the primary outcome. Secondary outcomes included lipid profile (low-density lipoprotein, high-density lipoprotein, and non–high-density lipoprotein cholesterol, and triglyceride levels), percentage of body fat, waist-hip ratio, fasting insulin and glucose levels, and blood pressure. Outcomes were assessed at months 0, 2, 6, and 12. The Tukey studentized range test was used to adjust for multiple testing.ResultsWeight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12-month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, −4.7 kg (95% confidence interval [CI], −6.3 to −3.1 kg), Zone, −1.6 kg (95% CI, −2.8 to −0.4 kg), LEARN, −2.6 kg (−3.8 to −1.3 kg), and Ornish, −2.2 kg (−3.6 to −0.8 kg). Weight loss was not statistically different among the Zone, LEARN, and Ornish groups. At 12 months, secondary outcomes for the Atkins group were comparable with or more favorable than the other diet groups.ConclusionsIn this study, premenopausal overweight and obese women assigned to follow the Atkins diet, which had the lowest carbohydrate intake, lost more weight and experienced more favorable overall metabolic effects at 12 months than women assigned to follow the Zone, Ornish, or LEARN diets. While questions remain about long-term effects and mechanisms, a low-carbohydrate, high-protein, high-fat diet may be considered a feasible alternative recommendation for weight loss.Trial Registrationclinicaltrials.gov Identifier: NCT00079573

/pdf/comparison-of-the-atkins-zone-ornish-and-learn-diets-for-9sdsg5tvsz.pdf

Comparison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and Related Risk Factors Among Overweight Premenopausal Women: The A TO Z Weight Loss Study: A Randomized Trial

Postmenopausal women are believed to have a higher risk of coronary artery disease than premenopausal women. In this study, we prospectively determined changes in coronary risk factors that were attributable to natural menopause in 541 healthy, initially premenopausal women 42 to 50 years of age. After approximately 2 1/2 years, 69 women had spontaneously stopped menstruating for at least 12 months, and 32 women had stopped natural menstruation and received hormone-replacement therapy for a period of at least 12 months. An equal number of age-matched premenopausal women in the study group served as controls. In women who had a natural menopause and did not receive hormone-replacement therapy, serum levels of high-density lipoprotein (HDL) cholesterol declined as compared with those of premenopausal controls (-0.09 vs. 0.00 mmol per liter; P = 0.01), and levels of low-density lipoprotein (LDL) cholesterol increased (+0.31 vs. +0.14 mmol per liter; P = 0.04). In menopausal women who received hormone-replacement therapy, HDL and LDL cholesterol levels did not change, but the levels of triglycerides (+0.42 vs. -0.04 mmol per liter; P less than 0.001), apolipoprotein A-I (+0.18 vs. +0.03 g per liter; P less than 0.01), and apolipoprotein A-II (+0.05 vs. -0.03 g per liter; P less than 0.05) increased as compared with premenopausal controls. Natural menopause did not affect blood pressure, plasma glucose or insulin levels, body weight, the total number of kilojoules consumed in the diet, or the total number of kilojoules expended in physical activity. These results suggest that a natural menopause has an unfavorable effect on lipid metabolism, which may contribute to an increase in the risk of coronary disease. Hormone-replacement therapy may prevent some of these changes.

https://www.nejm.org/doi/pdf/10.1056/NEJM198909073211004

G R Warnick

Papers

A comprehensive evaluation of the heparin-manganese precipitation procedure for estimating high density lipoprotein cholesterol.