Weight Loss - Obesity

[Michael Scally MD]

On September 17, 2012, VIVUS, Inc., or the Company, announced on the Company's web site at Qsymia™ (phentermine and topiramate extended-release) capsules CIV | Qsymia.com the U.S. market availability of Qsymia.
Qsymia™ (phentermine and topiramate extended-release) capsules CIV | Qsymia.com

 

[Michael Scally MD]

Rosenkilde M, Auerbach P, Reichkendler MH, Ploug T, Stallknecht BM, Sjodin A. Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise--a randomized controlled trial in overweight sedentary males. Am J Physiol Regul Integr Comp Physiol 2012;303(6):R571-9. Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise—a randomized controlled trial in overweight sedentary males

The amount of weight loss induced by exercise is often disappointing. A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited.

A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to approximately 30 and 60 min of daily aerobic exercise, respectively.

Body weight (MOD: -3.6 kg, P < 0.001; HIGH: -2.7 kg, P = 0.01) and fat mass (MOD: -4.0 kg, P < 0.001 and HIGH: -3.8 kg, P < 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: -39.6 Mcal, HIGH: -34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise.

In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.

 

[Michael Scally MD]

Haffer KN. Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice. J Anim Sci Biotechnol 2012;3(1):21. Effects of novel vaccines on weight loss in diet-induced-obese (DIO) mice

The purpose of the study was to test the therapeutic effects of novel vaccines for reducing weight gain and increasing weight loss in diet induced obesity (DIO) model. Male C57BL/6 J mice, fed a 60% Kcal fat diet for 8 weeks prior to the start of the study, were vaccinated via the intraperitoneal route with two formulations (JH17 & JH18) of chimeric-somatostatin vaccines at 1 and 22 days of the study. Control mice were injected with PBS. All mice continued to be feed the 60% Kcal fat diet for the 6 week study. Body weights were measured two times a week and food intake was measured weekly. At week 6, mice were euthanized and a terminal bleed was made and antibody levels to somatostatin and levels of insulin-like growth factor 1 (IGF-1) were determined.

Vaccination with both vaccine formulations induced a statistically significant body weight change over the study period, as compared with PBS controls. Percentage of baseline body weight was also significantly affected by vaccination during the study period. Vaccinates finished the study at 104% and 107% of baseline weight, JH17 & JH18 respectively, while untreated controls reached 115% of baseline weight. Food intake per mouse was similar in all mouse groups during the entire study. Control mice did not demonstrate any antibody titers to somatostatin, while all vaccinated mice had measurable antibody responses (> 1:500,000 titer). IGF-1 levels were not statistically significant among the groups, but were elevated in the JH18 vaccinates (mean 440.4 ng/mL) when compared with PBS controls (mean 365.6 ng/mL).

Vaccination with either JH17 or JH18 chimeric -somatostatin vaccines produced a statistically significant weight loss as compared with PBS controls (P < 0.0001), even though the DIO mice with continually fed a 60% Kcal fat diet. The weight loss/lower weight gain observations were even more significant, as all mice consumed similar amounts of food for the entire study. The presence of high levels of anti-somatostatin antibodies at 6 weeks was correlative with the weight observations and confirmed the success of vaccination.

 

[Michael Scally MD]

Noda K, Zhang B, Iwata A, et al. Lifestyle changes through the use of delivered meals and dietary counseling in a single-blind study. The STYLIST study. Circ J 2012;76(6):1335-44. https://www.jstage.jst.go.jp/article/circj/76/6/76_CJ-12-0164/_article

BACKGROUND: Dietary habits are associated with obesity, and both are important contributing factors to lifestyle-related diseases. The STYLIST study examined the effects of dietary counseling by registered dietitians and the delivery of proper calorie-controlled meals (UMIN Registration No: 000006582).

METHODS AND RESULTS: Two-hundred adult patients with hypertension and/or diabetes mellitus were randomly divided into 2 groups with/without dietary counseling and consumed an ordinary diet for 4 weeks. Each group was then subdivided into 2 groups with/without dietary counseling and received calorie-controlled lunch and dinner boxes for the next 4 weeks. The calories in the delivered meals were based on the subject's ideal body weight (BW) and physical activity level. BW, waist circumference, blood pressure, and laboratory data, including glycoalbumin, were measured at 0, 4, and 8 weeks. BW and the other parameters were significantly reduced during the study period in patients who received diet counseling in the ordinary diet period and/or delivered meal period but not in patients without dietary counseling, as assessed by linear mixed models for longitudinal data.

CONCLUSIONS: The combination of dietary counseling by dietitians and delivery of calorie-controlled meals was effective in reducing BW, as well as blood pressure and glycoalbumin, in patients with hypertension and/or diabetes mellitus.

 

[Michael Scally MD]

HHS OIG Reports Take Aim At Weight Loss and Immune Support Dietary Supplements
FDA Law Blog: HHS OIG Reports Take Aim At Weight Loss and Immune Support Dietary Supplements

The Department of Health and Human Services Office of Inspector General released two reports critical of dietary supplements in the weight loss and immune support categories. OIG focused on those categories because they were reported by experts to be among the most popular.

 

[Michael Scally MD]

Obesity & Cancer

The prevalence of obesity, a major risk factor for several chronic diseases, more than doubled between 1980 and 2000. The latest United States data suggest that the current prevalence of obesity in adults is leveling off around 35%, with another 33% of the adult population considered overweight. Approximately seven in 10 adults and three in 10 children in the United States exceed a healthy weight.

The obese phenotype often manifests in metabolic syndrome, which describes a state of metabolic dysregulation characterized by several factors: insulin resistance and hyperglycemia, dyslipidemia (higher triglycerides, lower high-density lipoprotein-cholesterol), increased waist circumference, and hypertension. We now know that this phenotype is associated with many types of cancer. In particular, study data sounded the alert to the magnitude of the obesity-cancer problem. In a very interesting article, authors found that 20% of cancer deaths can be attributed to overweight/obesity and 5% to lack of exercise. Thus, control of this one lifestyle-related risk factor has the potential to reduce the incidence of cancer by as much as a quarter.

The American Institute for Cancer Research and World Cancer Research Fund publishes systematic reviews, meta-analyses and recommendations based on the world’s cancer literature in their Expert Report on Food, Nutrition, Physical Activity, and the Prevention of Cancer, now in its second edition continuous updates online. As summarized in that report, many kinds of cancers are associated with obesity. Links have been established between obesity and with colorectal, kidney, liver/gall bladder, pancreatic, and esophageal cancers in both men and women; stomach and prostate cancers in men only; and postmenopausal breast, endometrial, uterine, and ovarian cancers in women only).

 

[Michael Scally MD]

Gadde KM, Kopping MF, Wagner H, Yonish GM, Allison DB, Bray GA. Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled Trial. Arch Intern Med. 2012;():1-8. JAMA Network | Archives of Internal Medicine | Zonisamide for Weight Reduction in Obese AdultsA 1-Year Randomized Controlled TrialZonisamide for Weight Reduction in Obese Adults

Background Obese individuals who have failed to achieve adequate weight loss with lifestyle changes have limited nonsurgical therapeutic options. We evaluated the efficacy and tolerability of zonisamide, an antiepileptic drug, for enhancing weight loss in obese patients receiving diet and lifestyle guidance.

Methods This was a 1-year, randomized, double-blind, placebo-controlled trial conducted from January 9, 2006, through September 20, 2011, at Duke University Medical Center. A total of 225 obese (mean [SD] body mass index, 37.6 [4.9]) participants included 134 women (59.6%) and 91 men (40.4%) without diabetes mellitus. (Body mass index is calculated as weight in kilograms divided by height in meters squared.) Interventions were daily dosing with placebo (n = 74), 200 mg of zonisamide (n = 76), or 400 mg of zonisamide (n = 75), in addition to diet and lifestyle counseling by a dietitian for 1 year. Primary outcome was change in body weight at 1 year.

Results Of the 225 randomized patients, 218 (96.9%) provided 1-year follow-up assessments. Change in body weight was ?4.0 kg (95% CI, ?5.8 to ?2.3 kg; least squares mean, ?3.7%) for placebo, ?4.4 kg (?6.1 to ?2.6 kg; ?3.9%; P = .79 vs placebo) for 200 mg of zonisamide, and ?7.3 kg (?9.0 to ?5.6 kg; ?6.8%; P = .009 vs placebo) for 400 mg of zonisamide. In the categorical analysis, 23 (31.1%) assigned to placebo, 26 (34.2%; P = .72) assigned to 200 mg of zonisamide, and 41 (54.7%;P = .007) assigned to 400 mg of zonisamide achieved 5% or greater weight loss; for 10% or greater weight loss, the corresponding numbers were 6 (8.1%), 17 (22.4%; P = .02), and 24 (32.0%;P < .001). Gastrointestinal, nervous system, and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo.

Conclusion Zonisamide at the daily dose of 400 mg moderately enhanced weight loss achieved with diet and lifestyle counseling but had a high incidence of adverse events.

 

[Michael Scally MD]

No Magic Bullet - Comment on “Zonisamide for Weight Reduction

Obesity is one of the most perplexing problems we treat as internists. The condition is associated with high morbidity and mortality, and yet the cause is one of the most basic of all human pleasures: eating. No wonder we are all hoping for a magic bullet.

Zonisamide at a daily dose of 400 mg, combined with diet and lifestyle counseling, provided moderately successful weight loss in this trial (7.3 kg [3.3 kg more than placebo] at 1 year) as it did in prior trials. The problem is that the adverse effects at this dose are substantial: 18.7% of patients experienced headache, 13.3% experienced nausea/vomiting, 9.3% experienced anxiety, and 10.7% experienced impaired memory.

This trial answered a sensible question: “Could zonisamide at 200 mg achieve meaningful weight loss without substantial adverse effects?” Unfortunately, the answer is no. Weight loss with the lower dose of zonisamide was almost identical to weight loss with placebo. Low-dose zonisamide produced adverse effects without a primary effect.

We need to continue to search for better weight loss aids. Until then, we have an effective and safe (albeit difficult to adhere to) regimen: eating less and exercising more.

Katz MH. Zonisamide: No Magic Bullet - Comment on “Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled Trial”. Arch Intern Med. 2012;():1. JAMA Network | Archives of Internal Medicine | ZonisamideNo Magic Bullet Comment on “Zonisamide for Weight Reduction in Obese Adults: A 1-Year Randomized Controlled Trial”Zonisamide

 

[Michael Scally MD]

 

[Michael Scally MD]

Yang T-L, Guo Y, Shen H, et al. Copy Number Variation on Chromosome 10q26.3 for Obesity Identified by a Genome-Wide Study. Journal of Clinical Endocrinology & Metabolism. Copy Number Variation on Chromosome 10q26.3 for Obesity Identified by a Genome-Wide Study

Background: Obesity is a highly heritable disease defined by high body mass index (BMI). However, a large proportion of the heritability of obesity remains unexplained. Copy number variations (CNVs) might contribute to the missing heritability of obesity.

Methods: We conducted genome-wide CNV analyses on obesity phenotypes, including BMI and body fat mass in a discovery sample of 2215 unrelated white subjects. After quality control, 314 CNVs were used for association tests. For significant CNVs identified, follow-up replication analyses were performed in three independent samples, including an unrelated sample of 1000 white subjects (OM sample), a family-based sample of 8385 white subjects (FHS sample), and an African-American sample of 1479 obesity cases and 1575 lean controls (AA sample).

Results: Genome-wide CNV analyses detected that a CNV located at 10q26.3, which, even after multiple testing corrections, showed a strong association with both BMI (P = 2.30 × 10?4, ? = 2.164) and body fat mass (P = 6.76 × 10?5, ? = 4.126). This CNV was successfully replicated in the three replication samples (OM sample: P = 0.0465 for BMI, 0.0435 for fat mass; FHS sample: P = 0.0038 for BMI; AA sample: P = 0.0023 for obesity). Quantitative PCR validated this CNV, which covers a gene, CYP2E1. The protein encoded by CYP2E1 involves the synthesis of cholesterol, steroids and other lipids, which may have a potential impact on obesity.

Conclusion: Our findings suggest the significant contribution of CNV10q26.3 to the pathogenesis of obesity.

 

[Michael Scally MD]

Metformin in Obesity

Kendall D, Vail A, Amin R, et al. Metformin in Obese Children and Adolescents: The MOCA Trial. Journal of Clinical Endocrinology & Metabolism. Metformin in Obese Children and Adolescents: The MOCA Trial

Context: Childhood obesity is increasingly associated with type 2 diabetes (T2D). Metformin reduces the risk for T2D in adult obese nondiabetic patients, but the evidence in obese children and young people is inconclusive.

Objective: The objective of the study was to assess the effect of metformin on body mass index SDscore (BMI-SDS), metabolic risk factors, and adipokines.

Design: This was a prospective, randomized, double-blind, placebo-controlled trial.

Setting: The study was conducted at six pediatric endocrine centers in the United Kingdom.

Participants: One hundred fifty-one obese children and young people with hyperinsulinemia and/or impaired fasting glucose or impaired glucose tolerance (metformin: 74, placebo: 77). The study was comprised of 67.5% females, 65.6% postpubertal individuals, and 23.8% British Asian or Afro-Caribbean participants. The age range was 8–18 yr, the mean age was 13.7 (SD 2.3) yr, and the mean BMI-SDS was +3.4 (SD 0.5).

Interventions: The intervention included metformin 1 g in the morning and 500 mg in the evening vs.placebo for 6 months.

Main Outcome Measure: The main outcome measure was a reduction in BMI-SDS at 6 months. Secondary outcomes included insulin and glucose levels from oral glucose tolerance tests, alanine aminotransferase (ALT), and adiponectin to leptin ratio (ALR) at 3 and 6 months.

Results: Metformin was associated with a significant reduction in BMI-SDS compared with placebo at 6 months [mean difference ?0.1 SD (95% confidence interval ?0.18 to ?0.02), P = 0.02]. Significant improvements at 3 months were found in the metformin group: fasting glucose, ?0.16 mmol/liter (?0.31 to ?0.00), P = 0.047; ALT, 19% (5–36%), P = 0.008; and ALR, 32% (4–67%), P = 0.02.

Conclusions: Metformin therapy has a beneficial treatment effect over placebo for BMI-SDS, fasting glucose, ALT, and ALR ratio at 3 months, with changes in BMI-SDS sustained at 6 months.

 

[Michael Scally MD]

Lee H, Asmaa A, Helen JM, Wayne D, Skeaff CM, Carolyn DS. Effect of reducing total fat intake on body weight: systematic review and meta-analysis of randomised controlled trials and cohort studies. BMJ 2012;345. Effect of reducing total fat intake on body weight: systematic review and meta-analysis of randomised controlled trials and cohort studies | BMJ

Objective To investigate the relation between total fat intake and body weight in adults and children.

Design Systematic review and meta-analysis of randomised controlled trials and cohort studies.

Data sources Medline, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials to June 2010.

Inclusion criteria Randomised controlled trials and cohort studies of adults or children that compared lower versus usual total fat intake and assessed the effects on measures of body fatness (body weight, body mass index, or waist circumference) after at least six months (randomised controlled trials) or one year (in cohorts). Randomised controlled trials with any intention to reduce weight in participants or confounded by additional medical or lifestyle interventions were excluded.

Data extraction Data were extracted and validity was assessed independently and in duplicate. Random effects meta-analyses, subgroups, sensitivity analyses, and metaregression were done.

Results 33 randomised controlled trials (73?589 participants) and 10 cohort studies were included, all from developed countries. Meta-analysis of data from the trials suggested that diets lower in total fat were associated with lower relative body weight (by 1.6 kg, 95% confidence interval ?2.0 to ?1.2 kg, I2=75%, 57?735 participants). Lower weight gain in the low fat arm compared with the control arm was consistent across trials, but the size of the effect varied. Metaregression suggested that greater reduction in total fat intake and lower baseline fat intake were associated with greater relative weight loss, explaining most of the heterogeneity. The significant effect of a low fat diet on weight was not lost in sensitivity analyses (including removing trials that expended greater time and attention on low fat groups). Lower total fat intake also led to lower body mass index (?0.51 kg/m2, 95% confidence interval ?0.76 to ?0.26, nine trials, I2=77%) and waist circumference (by 0.3 cm, 95% confidence interval ?0.58 to ?0.02, 15?671 women, one trial). There was no suggestion of negative effects on other cardiovascular risk factors (lipid levels or blood pressure). GRADE assessment suggested high quality evidence for the relation between total fat intake and body weight in adults. Only one randomised controlled trial and three cohort studies were found in children and young people, but these confirmed a positive relation between total fat intake and weight gain.

Conclusions There is high quality, consistent evidence that reduction of total fat intake has been achieved in large numbers of both healthy and at risk trial participants over many years. Lower total fat intake leads to small but statistically significant and clinically meaningful, sustained reductions in body weight in adults in studies with baseline fat intakes of 28-43% of energy intake and durations from six months to over eight years. Evidence supports a similar effect in children and young people.

 

[Michael Scally MD]

Xiao D, Shi D, Yang D, Barthel B, Koch TH, Yan B. CARBOXYLESTERASE-2 IS A HIGHLY SENSITIVE TARGET OF THE ANTIOBESITY AGENT ORLISTAT WITH PROFOUND IMPLICATIONS IN THE ACTIVATION OF ANTICANCER PRODRUGS. Biochemical Pharmacology. ScienceDirect.com - Biochemical Pharmacology - CARBOXYLESTERASE-2 IS A HIGHLY SENSITIVE TARGET OF THE ANTIOBESITY AGENT ORLISTAT WITH PROFOUND IMPLICATIONS IN THE ACTIVATION OF ANTICANCER PRODRUGS

Orlistat has been the most used anti-obesity drug and the mechanism of its action is to reduce lipid absorption by inhibiting gastrointestinal lipases. These enzymes, like carboxylesterases (CESs), structurally belong to the ?/? hydrolase fold superfamily. Lipases and CESs are functionally related as well. Some CESs (e.g., human CES1) have been shown to hydrolyze lipids. This study was designed to test the hypothesis that orlistat inhibits CESs with higher potency toward CES1 than CES2, a carboxylesterase with little lipase activity. Liver microsomes and recombinant CESs were tested for the inhibition of the hydrolysis of standard substrates and the anticancer prodrugs pentyl carbamate of p-aminobenzyl carbamate of doxazolidine (PPD) and irinotecan. Contrary to the hypothesis, orlistat at 1 nM inhibited CES2 activity by 75% but no inhibition on CES1, placing CES2 one of the most sensitive targets of orlistat. The inhibition varied among some CES2 polymorphic variants. Pretreatment with orlistat reduced the cell killing activity of PPD. Certain mouse but not rat CESs were also highly sensitive. CES2 is responsible for the hydrolysis of many common drugs and abundantly expressed in the gastrointestinal track and liver. Inhibition of this carboxylesterase probably presents a major source for altered therapeutic activity of these medicines if co-administered with orlistat. In addition, orlistat has been linked to various types of organ toxicities, and this study provides an alternative target potentially involved in these toxicological responses.


Popular Weight Loss Drug May Cause Permanent Liver and Kidney Damage
Popular Weight Loss Drug May Cause Permanent Liver and Kidney Damage - Forbes


Most Popular Weight-Loss Drug Strongly Alters Other Drug Therapies, Study Suggests
Most popular weight-loss drug strongly alters other drug therapies, study suggests

 

[Michael Scally MD]

Muller TD, Lee SJ, Jastroch M, et al. p62 Links ?-adrenergic input to mitochondrial function and thermogenesis. The Journal of Clinical Investigation 2012;123(1):469-78. JCI - p62 Links ?-adrenergic input to mitochondrial function and thermogenesis

The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to ?-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1?, DIO2, NRF1, CYTC, COX2, ATP5?, and UCP1. p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.

 

[sallyjoseph]

Interesting post regarding the weight loss.

 

[Michael Scally MD]

Vu L, Switzer NJ, De Gara C, Karmali S. Surgical interventions for obesity and metabolic disease. Best Practice & Research Clinical Endocrinology & Metabolism. ScienceDirect.com - Best Practice & Research Clinical Endocrinology & Metabolism - Surgical interventions for obesity and metabolic disease

Obesity continues to be a growing problem in both the developed and the developing world. Its strong link with co-morbid conditions such as type 2 diabetes, hypertension, obstructive sleep apnea, and depression presents an increasing strain on health care systems around the world. Diet and exercise alone has been shown to be largely ineffective at managing obesity. Surgery is the only evidence-based method of allowing morbidly obese patients to lose weight and to maintain this weight loss. Weight-reduction in obese individuals from bariatric surgery has also been found to markedly improve obesity-related co-morbid conditions, particularly, type 2-diabetes. Diabetic remission from bariatric surgery has resulted in the inclusion of bariatric surgery, by the International Diabetes Taskforce, as a treatment modality for type-2 diabetes. This consensus statement named four surgical options that have been found to be effective in both weight-loss and in inducing diabetes remission. These four surgical procedures lead to weight-loss through restrictive and malabsorptive mechanisms. Each specific operation has a different level of efficacy in inducing weight-loss and diabetic remission, as well as distinct types and rates of complications. This article reviews the best evidence that exists for the effectiveness and complications of these four operations.

 

[Michael Scally MD]

Garaulet M, Gomez-Abellan P, Alburquerque-Bejar JJ, Lee YC, Ordovas JM, Scheer FAJL. Timing of food intake predicts weight loss effectiveness. Int J Obes. International Journal of Obesity - Abstract of article: Timing of food intake predicts weight loss effectiveness

Background: There is emerging literature demonstrating a relationship between the timing of feeding and weight regulation in animals. However, whether the timing of food intake influences the success of a weight-loss diet in humans is unknown.

Objective: To evaluate the role of food timing in weight-loss effectiveness in a sample of 420 individuals who followed a 20-week weight-loss treatment.

Methods: Participants (49.5% female subjects; age (mean±s.d.): 42±11 years; BMI: 31.4±5.4?kg?m?2) were grouped in early eaters and late eaters, according to the timing of the main meal (lunch in this Mediterranean population). 51% of the subjects were early eaters and 49% were late eaters (lunch time before and after 1500 hours, respectively), energy intake and expenditure, appetite hormones, CLOCK genotype, sleep duration and chronotype were studied.

Results: Late lunch eaters lost less weight and displayed a slower weight-loss rate during the 20 weeks of treatment than early eaters (P=0.002). Surprisingly, energy intake, dietary composition, estimated energy expenditure, appetite hormones and sleep duration was similar between both groups. Nevertheless, late eaters were more evening types, had less energetic breakfasts and skipped breakfast more frequently that early eaters (all; P<0.05). CLOCK rs4580704 single nucleotide polymorphism (SNP) associated with the timing of the main meal (P=0.015) with a higher frequency of minor allele (C) carriers among the late eaters (P=0.041). Neither sleep duration, nor CLOCK SNPs or morning/evening chronotype was independently associated with weight loss (all; P>0.05).

Conclusions: Eating late may influence the success of weight-loss therapy. Novel therapeutic strategies should incorporate not only the caloric intake and macronutrient distribution—as is classically done—but also the timing of food.

 

[Michael Scally MD]

Casazza K, Fontaine KR, Astrup A, et al. Myths, Presumptions, and Facts about Obesity. New England Journal of Medicine 2013;368(5):446-54. MMS: Error

BACKGROUND - Many beliefs about obesity persist in the absence of supporting scientific evidence (presumptions); some persist despite contradicting evidence (myths). The promulgation of unsupported beliefs may yield poorly informed policy decisions, inaccurate clinical and public health recommendations, and an unproductive allocation of research resources and may divert attention away from useful, evidence-based information.

METHODS - Using Internet searches of popular media and scientific literature, we identified, reviewed, and classified obesity-related myths and presumptions. We also examined facts that are well supported by evidence, with an emphasis on those that have practical implications for public health, policy, or clinical recommendations.

RESULTS - We identified seven obesity-related myths concerning the effects of small sustained increases in energy intake or expenditure, establishment of realistic goals for weight loss, rapid weight loss, weight-loss readiness, physical-education classes, breast-feeding, and energy expended during sexual activity. We also identified six presumptions about the purported effects of regularly eating breakfast, early childhood experiences, eating fruits and vegetables, weight cycling, snacking, and the built (i.e., human-made) environment. Finally, we identified nine evidence-supported facts that are relevant for the formulation of sound public health, policy, or clinical recommendations.

CONCLUSIONS - False and scientifically unsupported beliefs about obesity are pervasive in both scientific literature and the popular press.

 

[Michael Scally MD]

Changes in Cardiovascular Risk Associated With Phentermine and Topiramate [Qsymia]

Davidson MH, Tonstad S, Oparil S, Schwiers M, Day WW, Bowden CH. Changes in Cardiovascular Risk Associated With Phentermine and Topiramate Extended-Release in Participants With Comorbidities and a Body Mass Index >/= 27 kg/m2. The American Journal of Cardiology. ScienceDirect.com - The American Journal of Cardiology - Changes in Cardiovascular Risk Associated With Phentermine and Topiramate Extended-Release in Participants With Comorbidities and a Body Mass Index ?27 kg/m2

The aim of this analysis was to evaluate changes in cardiovascular risk factors in obese patients with dyslipidemia and/or hypertension receiving phentermine (PHEN) and topiramate extended-release (TPM ER).

In the 56-week, randomized, double-blind, placebo-controlled, multicenter CONQUER trial, PHEN/TPM ER demonstrated significant weight loss compared with placebo in overweight or obese participants with ?2 weight-related co-morbidities. Participants with body mass indexes of 27 to 45 kg/m2were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg; participants also received lifestyle modification counseling. Primary end points were percentage weight loss and the proportion of participants achieving ?5% weight loss. Additional end points were changes in lipid variables in the dyslipidemia population and blood pressure in the hypertensive population, stratified by treatment and magnitude of weight loss.

PHEN/TPM ER produced significantly greater dose-related mean percentage weight loss compared with placebo in the subgroups of participants with dyslipidemia and those with hypertension. Regardless of treatment group assignment, participants with dyslipidemia who lost ?5% of their baseline weight experienced significantly greater reductions in triglycerides (?14.5% to ?39.8%), and in non–high-density lipoprotein cholesterol (?9.4% to ?14.8%) than those losing <5% of their weight (p <0.05). Similarly, participants with hypertension at baseline showed reduced systolic blood pressure by ?7.5 to ?11.8 mm Hg (p <0.001 vs those with <5% weight loss).

In conclusion, the dose-related weight loss induced by PHEN/TPM ER treatment was accompanied by significant improvements in cardiovascular disease risk factors in participants who had dyslipidemia or hypertension at baseline, suggesting that facilitating weight loss by augmenting lifestyle changes with pharmacotherapies may decrease the risk for cardiovascular disease in obese and overweight patients with co-morbidities.

 

[Michael Scally MD]

Obesity-Induced Insulin Resistance

Testosterone deficiency contributes to tissue specific mechanisms involved in the development of insulin resistance in liver, adipose and muscle tissue, and promotes inflammation (green arrows). TRT may potentially improve the negative consequences of tissue specific insulin insensitivity and improve metabolic function.

Chronic excessive dietary fat and carbohydrate intake coupled with a decrease in energy expenditure leads to a sustained rise in circulating free fatty acids (FFA) and blood glucose concentration.

Excess FFA (yellow arrows) are incorporated into adipocyte triglyceride storage increasing visceral and subcutaneous fat mass. Adipose accumulation promotes the release of FFA into the circulation via lipolysis and these are taken up by muscle and liver in a ‘spillover’ effect.

With accumulation of intramyocellular lipid, insulin-mediated skeletal muscle glucose uptake and utilization is impaired along with decreased glycogen synthesis and lipid oxidation.

As a result, excess glucose is diverted to the liver. In the liver, increased liver lipid also impairs the ability of insulin to regulate gluconeogenesis and activate glycogen synthesis. Hepatic lipogenesis further increases lipid content and can lead to hepatic steatosis.

Impaired insulin action in the adipose tissue allows for increased lipolysis, which additionally promotes re-esterification of lipids in other tissues (such as liver and muscle) and further exacerbates insulin resistance.

At the same time, adipose-derived inflammatory mediators contribute to the development of tissue insulin resistance (dark blue arrows). In particular, IL-6 and TNF? inhibit the normal tyrosine phosphorylation of IRS-1 and downstream signaling in hepatic tissue reducing insulin sensitivity. Similarly, TNF? promotes insulin resistance in skeletal muscle via IRS-1 degradation and inhibition of insulin signaling.

Although IL-6 has been shown to exert some insulin sensitizing effects in muscle, evidence also indicates a negative impact on insulin action and glucose homeostasis by decreasing gene transcription of IRS-1, Glut4 and PPAR? as well as IRS-1 activity, and thus reducing insulin-stimulated glucose uptake.

Hyperglycemia Ensues.