Title: Physical Activity and Weight Gain Prevention
Topic: Prevention/Vascular
Date Posted: 3/31/2010
Author(s): Lee IM, Djousse L, Sesso HD, Wang L, Buring JE.
Citation: JAMA 2010;303:1173-1179.
Clinical Trial: No
Study Question: In 2008, federal guidelines recommended at least 150 minutes per week (7.5 metabolic equivalent [MET] hours per week) of moderate-intensity activity for “substantial health benefits.” What is the association of physical activity with long-term weight changes among women consuming a usual diet?
Methods: This prospective cohort study involved 34,079 healthy women participating in the Women’s Health Study from 1992-2007. At baseline and years 3, 6, 8, 10, 12, and 13, women reported their physical activity and body weight. Women were classified as expending <7.5, 7.5 to <21, and ≥21 MET hours per week of activity at each time. Repeated-measures regression prospectively examined physical activity and weight change over intervals averaging 3 years.
Results: At baseline, mean age was 54.2 years; about 50% of the women expended <7.5 MET hours per week; mean body mass index (BMI) was 26 kg/m2; 94% were white; and 40% were on hormone therapy. Mean (standard deviation) energy intake was similar between groups (~1725 [542] kcal/d). Women gained a mean of 2.6 kg throughout the study. A multivariate analysis comparing women expending ≥21 MET hours per week with those expending from 7.5 to <21 MET hours per week showed that the latter group gained a mean of 0.11 (0.04) kg (p = 0.003) over a mean interval of 3 years, and those expending <7.5 MET hours per week gained 0.12 (0.04) kg (p = 0.002). There was a significant interaction with BMI; an inverse dose-response relation between activity levels and weight gain among women with a BMI of <25 kg/m2 (p for trend < 0.001), but no relation among women with a BMI from 25-29.9 (p for trend = 0.56) or with a BMI of 30.0 kg/m2 or higher (p for trend = 0.50). A total of 4,540 women (13.3%) with a BMI lower than 25 kg/m2 at study start successfully maintained their weight by gaining <2.3 kg throughout. Their mean activity level over the study was 21.5 MET hours per week (~60 minutes a day of moderate-intensity activity).
Conclusions: Among women consuming a usual diet, physical activity was associated with less weight gain only among women whose BMI was lower than 25 kg/m2. Women successful in maintaining normal weight and gaining fewer than 2.3 kg over 13 years averaged approximately 60 minutes a day of moderate-intensity activity throughout the study.
Perspective: How many women 52 years of age would exercise 60 minutes a day in order to not gain more than 5 pounds over 13 years? One per 1,000? The authors had two posits, neither of which makes sense: 1) once overweight, it may be too late because physical activity is not associated with less weight gain; 2) sustaining high levels of physical activity (~60 minutes a day) is needed to successfully maintain normal BMI and prevent weight gain. While MET hours per week of activity is a reasonable way to estimate kcal/day of energy expenditure, over 95% of kcal of energy is expended at rest or during sleep. Weight gain in middle-aged men and women is highly related to increasing energy intake, which was not measured in these women. Adding the equivalent of one slice of bread per day (100 kcal) could on average result in ~10 pounds of weight gain in 1 year. The impact of supersizing and fast foods cannot be overcome by exercise. Melvyn Rubenfire, M.D., F.A.C.C.
Title: Mipomersen, an Apolipoprotein B Synthesis Inhibitor, for Lowering of LDL Cholesterol Concentrations in Patients With Homozygous Familial Hypercholesterolaemia: A Randomised, Double-Blind, Placebo-Controlled Trial
Topic: Prevention/Vascular
Date Posted: 3/31/2010
Author(s): Raal FJ, Santos RD, Blom DJ, et al.
Citation: Lancet 2010;375:998-1006.
Clinical Trial: yes
Study Question: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder in which both low-density lipoprotein (LDL)-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. Is mipomersen, an anti-sense inhibitor of apolipoprotein (apo) B synthesis, as effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with HoFH?
Methods: A randomized, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics. Patients ages 12 years and older with clinical diagnosis or genetic confirmation of HoFH, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously or placebo weekly for 26 weeks. The primary endpoint was percentage change in LDL cholesterol concentration from baseline with analysis by intention to treat.
Results: Mean (standard deviation) age was 31 (12) years and seven were younger than 18 years old; 57% were women; 57% were true HoFH and 26% compound heterozygotes; 74% were on maximal statin dose + ezetimibe. Mean values for lipids were similar between groups: LDL cholesterol 425 mg/dl and apo B 270 mg/dl. Thirty-four patients were assigned to mipomersen and 17 to placebo. Forty-five patients completed the 26-week treatment period (28 mipomersen, 17 placebo). The mean percentage change in LDL-C was significantly greater with mipomersen (-24.7%, 95% confidence interval, -31.6 to -17.7) than with placebo (-3.3%, -12.1 to 5.5; p = 0.0003). The treatment effect of mipomersen on LDL cholesterol varied from -82% to +2% and with placebo varied from -30% to +40%. The most common adverse events were injection-site reactions (26 [76%] patients in the mipomersen group vs. four [24%] in the placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal.
Conclusions: Inhibition of apo B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous FH who are already receiving lipid-lowering drugs, including high-dose statins.
Perspective: The potential use of anti-sense oligonucleotides that inhibit protein synthesis by binding to mRNA is quite appealing for many conditions, particularly anti-apo B synthesis in FH where statins are limited in their ability to up-regulate LDL receptor activity. The 25% reduction in LDL cholesterol with mipomersen seems modest, but represents about a 100 mg/dl reduction. If mipomersen is safe, it has great potential in those refractory to statins, but more importantly those who are statin intolerant. Melvyn Rubenfire, M.D., F.A.C.C.