Objective To test the effectiveness and safety of a total diet replacement (TDR) programme for routine treatment of obesity in a primary care setting.
Design Pragmatic, two arm, parallel group, open label, individually randomised controlled trial.
Setting 10 primary care practices in Oxfordshire, UK.
Participants 278 adults who were obese and seeking support to lose weight: 138 were assigned to the TDR programme and 140 to usual care. 73% of participants were re-measured at 12 months.
Interventions The TDR programme comprised weekly behavioural support for 12 weeks and monthly support for three months, with formula food products providing 810 kcal/day (3389 kJ/day) as the sole food during the first eight weeks followed by reintroduction of food. Usual care comprised behavioural support for weight loss from a practice nurse and a diet programme with modest energy restriction.
Main outcome measures The primary outcome was weight change at 12 months analysed as intention to treat with mixed effects models. Secondary outcomes included biomarkers of cardiovascular and metabolic risk. Adverse events were recorded.
Results Participants in the TDR group lost more weight (−10.7 kg) than those in the usual care group (−3.1 kg): adjusted mean difference −7.2 kg (95% confidence interval −9.4 to −4.9 kg). 45% of participants in the TDR group and 15% in the usual care group experienced weight losses of 10% or more. The TDR group showed greater improvements in biomarkers of cardiovascular and metabolic risk than the usual care group. 11% of participants in the TDR group and 12% in the usual care group experienced adverse events of moderate or greater severity.
Conclusions Compared with regular weight loss support from a practice nurse, a programme of weekly behavioural support and total diet replacement providing 810 kcal/day seems to be tolerable, and leads to substantially greater weight loss and greater improvements in the risk of cardiometabolic disease.
Objective To determine the efficacy of high dose folic acid supplementation for prevention of pre-eclampsia in women with at least one risk factor: pre-existing hypertension, prepregnancy diabetes (type 1 or 2), twin pregnancy, pre-eclampsia in a previous pregnancy, or body mass index ≥35.
Design Randomised, phase III, double blinded international, multicentre clinical trial.
Setting 70 obstetrical centres in five countries (Argentina, Australia, Canada, Jamaica, and UK).
Participants 2464 pregnant women with at least one high risk factor for pre-eclampsia were randomised between 2011 and 2015 (1144 to the folic acid group and 1157 to the placebo group); 2301 were included in the intention to treat analyses.
Intervention Eligible women were randomised to receive either daily high dose folic acid (four 1.0 mg oral tablets) or placebo from eight weeks of gestation to the end of week 16 of gestation until delivery. Clinicians, participants, adjudicators, and study staff were masked to study treatment allocation.
Main outcome measure The primary outcome was pre-eclampsia, defined as hypertension presenting after 20 weeks’ gestation with major proteinuria or HELLP syndrome (haemolysis, elevated liver enzymes, low platelets).
Results Pre-eclampsia occurred in 169/1144 (14.8%) women in the folic acid group and 156/1157 (13.5%) in the placebo group (relative risk 1.10, 95% confidence interval 0.90 to 1.34; P=0.37). There was no evidence of differences between the groups for any other adverse maternal or neonatal outcomes.
Conclusion Supplementation with 4.0 mg/day folic acid beyond the first trimester does not prevent pre-eclampsia in women at high risk for this condition.
Objective To examine the effect of supplementation with n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) in pregnancy on anthropometry and body composition in offspring.
Design Double blinded, randomised controlled trial.
Setting Copenhagen Prospective Studies on Asthma in Childhood2010 cohort.
Participants 736 pregnant women and their offspring.
Intervention n-3 LCPUFA (fish oil) or control (olive oil) daily from pregnancy week 24 until one week after birth.
Main outcome measures Height/length, weight, head, and waist measurements and body composition from dual energy x ray absorptiometry (all pre-specified secondary endpoints of the n-3 LCPUFA trial; the primary outcome for the trial was persistent wheeze/asthma).
Results The mean body mass index (BMI) z score was increased between age 0 and 6 years in the fish oil supplementation group compared with the control group (0.14 (95% confidence interval 0.04 to 0.23); P=0.006). At 6 years, supplementation was associated with a higher BMI z score (0.19 (0.06 to 0.32); P=0.004), a higher weight/height (3.48 (0.38 to 6.57) g/cm; P=0.03), and a larger waist circumference (0.6 (0.0 to 1.2) cm; P=0.04) but not a higher proportion of obese children, using International Obesity Task Force grades. The dual energy x ray absorptiometry scan at age 6 years showed a higher total mass (395.4 (86.6 to 704.3) g; P=0.01) in the supplementation versus the control group, explained by a higher lean mass (280.7 (98.9 to 462.4) g; P=0.002), a higher bone mineral content (10.3 (2.3 to 18.1) g; P=0.01), and a non-significantly higher fat mass (116.3 (−92.9 to 325.5) g; P=0.28), but no differences were seen in total body fat or lean mass percentage.
Conclusion Fish oil supplementation from the 24th week of pregnancy led to a higher BMI in the offspring from 0 to 6 years of age but not an increased risk of obesity at age 6. The body composition at age 6 years in children given fish oil supplementation was characterised by a proportional increase in lean, bone, and fat mass suggesting a general growth stimulating effect of n-3 LCPUFA.
Questions Is there a difference in biomarkers of smoke exposure between reducing nicotine content of cigarettes immediately vs gradually?
Findings In this randomized clinical trial of 1250 smokers, immediate compared with gradual reduction to very low nicotine content cigarettes or with a control smoking group significantly reduced exposure (area under the concentration curve) to breath carbon monoxide (difference, 4.06 ppm and 3.38 ppm for immediate vs gradual reduction group and immediate reduction vs control group, respectively), acrolein (difference, 17% and 19%), and phenanthrene tetraol (difference, 12% and 14%); there were no significant differences between the gradual and control groups.
Meaning Immediate reduction in nicotine content of cigarettes provided the greatest reduction in biomarkers of smoke exposure over time.
Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined.
We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization [extended major cardiovascular events]) was assessed for superiority at the end of the trial.
At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P<0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P<0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04).
In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA–TIMI 61 ClinicalTrials.gov number, NCT02019264.)
Reference: N Engl J Med 2018; 379:1107-1117
Baloxavir marboxil is a selective inhibitor of influenza cap-dependent endonuclease. It has shown therapeutic activity in preclinical models of influenza A and B virus infections, including strains resistant to current antiviral agents.
We conducted two randomized, double-blind, controlled trials involving otherwise healthy outpatients with acute uncomplicated influenza. After a dose-ranging (10 to 40 mg) placebo-controlled trial, we undertook a placebo- and oseltamivir-controlled trial of single, weight-based doses of baloxavir (40 or 80 mg) in patients 12 to 64 years of age during the 2016–2017 season. The dose of oseltamivir was 75 mg twice daily for 5 days. The primary efficacy end point was the time to alleviation of influenza symptoms in the intention-to-treat infected population.
In the phase 2 trial, the median time to alleviation of influenza symptoms was 23.4 to 28.2 hours shorter in the baloxavir groups than in the placebo group (P<0.05). In the phase 3 trial, the intention-to-treat infected population included 1064 patients; 84.8 to 88.1% of patients in each group had influenza A(H3N2) infection. The median time to alleviation of symptoms was 53.7 hours (95% confidence interval [CI], 49.5 to 58.5) with baloxavir, as compared with 80.2 hours (95% CI, 72.6 to 87.1) with placebo (P<0.001). The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with greater reductions in viral load 1 day after initiation of the regimen than placebo or oseltamivir. Adverse events were reported in 20.7% of baloxavir recipients, 24.6% of placebo recipients, and 24.8% of oseltamivir recipients. The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 2.2% and 9.7% of baloxavir recipients in the phase 2 trial and phase 3 trial, respectively.
Single-dose baloxavir was without evident safety concerns, was superior to placebo in alleviating influenza symptoms, and was superior to both oseltamivir and placebo in reducing the viral load 1 day after initiation of the trial regimen in patients with uncomplicated influenza. Evidence for the development of decreased susceptibility to baloxavir after treatment was also observed. (Funded by Shionogi; JapicCTI number, 153090, and CAPSTONE-1 ClinicalTrials.gov number, NCT02954354.)
Reference: N Engl J Med 2018; 379:913-923