Smoking, Alcohol and Obesity Increase Risk of Malignancies + Staff Morale (Humor)

S-M Wang et al. The American Journal of Gastroenterology: September 2021 – Volume 116 – Issue 9 – p 1844-1852. Open Access: Population Attributable Risks of Subtypes of Esophageal and Gastric Cancers in the United States

This study examined population risks for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia adenocarcinoma (GCA), and gastric noncardia adenocarcinoma (GNCA).

“We prospectively examined the associations for risk factors and these cancers in 490,605 people in the National Institutes of Health-the American Association of Retired Persons Diet and Health cohort Diet and Health Study cohort from 1995 to 2011.”

Key findings:

My take: Tobacco, Obesity and Alcohol are associated with increased risk for a large proportion of esophageal and gastric cancers in the United States

Related article: VK Rustgi et al. Gastroenterol 2021; 161: 171-184. Open Access: Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity

Key findings:

  • The IPTW (inverse probability of treatment weighting)-adjusted risk of any cancer and obesity-related cancer was reduced by 18% (hazard ratio, 0.82; 95% CI, 0.76–0.89) and 25% (hazard ratio, 0.65; 95% CI, 0.56–0.75), respectively, in patients with versus without bariatric surgery.
  • In cancer-specific models, bariatric surgery was associated with significant risk reductions for colorectal, pancreatic, endometrial, thyroid cancers, hepatocellular carcinoma, and multiple myeloma.

Link: Improving Morale (53 seconds)

Encouraging Safety Data for Ustekinumab & ESPGHAN Obesity Position Paper

WJ Sandborn et al. Inflamm Bowel Dis 2021; 27: 994-1007. Full text: Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year; this included 2574 patients (1733 patient-years of follow-up)

Key Safety findings –Events per 100 patient years -placebo vs ustekinumab respectively:

  • Adverse events: 165.99 [95% CI, 155.81–176.67] vs 118.32 [95% CI, 113.25–123.55])
  • Serious AEs: 27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51])
  • Infections 80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21])
  • Serious infections: 5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19])
  • Malignancies excluding nonmelanoma skin cancer: 0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83])
  • Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12

More key findings:

  • No cases of progressive multifocal leukoencephalopathy or reversible posterior leukoencephalopathy
  • Antibodies to ustekinumab were identified in 3.6% of patients

My take: This study showed similar safety between ustekinumab and placebo, but is limited by short followup. The authors note that 5-year data from ustekinumab’s use with psoriasis has found no safety signals for malignancy.

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Unrelated article: E Verduci et al. JPGN 2021; 72: 769-783: Full text: Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition

Obesity and Cellular Aging in Childhood

A provocative study (MJ Baskind et al. J Pediatr 2021; 233: 141-149. Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length) suggests that obesity in infancy can result in shortened telomere length, which is a cumulative marker for cellular aging. Also, leukocyte telomere length (LTL) is associated with known risk factors for cardiometabolic disease, including obesity and smoking

The authors prospectively studied a group of 97 woman-infant dyads from the Latinx, Eating and Diabetes cohort. Key findings:

  • Obesity at 6 months was negatively associated (β = −0.21; P < .001) with leukocyte telomere length
  • However, there was a lack of association between obesity at earlier ages (2-5 years) and preschooler LTL in the same cohort
  • Any breastfeeding at 6 months was positively associated with leukocyte telomere length

From the associated editorial: JL Buxton, fulltext: Early Warning Signs? Infant Obesity and Accelerated Cellular Aging “These results are based on data from a relatively small sample and await replication in larger cohorts recruited from different populations.”

My take: This study shows that obesity could be affecting our bodies in ways that most of us have never contemplated.

Aerial view of the “the quicksands” off the coast of Key West:

FDA Approval of Semiglutide for Obesity & AGA Recommends Intragastric Balloons for Adults with Obesity

June 4, 2021: FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014

“The U.S. Food and Drug Administration approved Wegovy (semaglutide) injection (2.4 mg once weekly) for chronic weight management in adults with obesity or overweight with at least one weight-related condition (such as high blood pressure, type 2 diabetes, or high cholesterol), for use in addition to a reduced calorie diet and increased physical activity…The drug is indicated for chronic weight management in patients with a body mass index (BMI) of 27 kg/m2 or greater who have at least one weight-related ailment or in patients with a BMI of 30 kg/m2 or greater… The largest placebo-controlled trial enrolled adults without diabetes. Individuals who received Wegovy lost an average of 12.4% of their initial body weight compared to individuals who received placebo” 


T Muniraj et al. Gastroenterol 2021; 160-1799-1808. Full text: AGA Clinical Practice Guidelines on Intragastric Balloons in the Management of Obesity

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Are We On the Verge of Pharmacologic Management of Obesity (Again)?

In the 1990s, the combination of fenfluramine/phentermine was popularized as a treatment for obesity. Fenfluarmine, though, was shown to cause potentially fatal pulmonary hypertension and heart valve problems, which eventually led to its withdrawal and legal damages of over $13 billion (per Wikipedia: fenfluramine/phentermine).

Now, glucagon-like peptide-1 (GLP-1) receptor agonists, like liraglutide, are showing promise as agents to promote weight loss, primarily by inhibiting appetite. JR Lundrgen et al (NEJM 2021; 384: 1719-1730. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined) show that liraglutide can promote weight loss, especially if combined with exercise.

Methods: After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorous–intensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day-SC injection) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group)

Key findings:

  • After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg.
  • At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, −4.1 kg (95% confidence interval [CI], −7.8 to −0.4; P=0.03); in the liraglutide group, −6.8 kg (95% CI, −10.4 to −3.1; P<0.001); and in the combination group, −9.5 kg (95% CI, −13.1 to −5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, −5.4 kg; 95% CI, −9.0 to −1.7; P=0.004) but not significantly more than monotherapy with liraglutide (−2.7 kg; 95% CI, −6.3 to 0.8; P=0.13)
  • The side effects of decreased appetite, dizziness, increased heart rate and palpitations were more common in those receiving liraglutide; palpitations were evident in 12% of the liraglutide monotherapy group and 4% of the combination (with exercise) group.

The details of the exercise program are detailed in the methods section; all participants were assigned an instructor and expected to do a minimum of 150 minutes per week of moderate-intensity aerobic physical activity or 75 minutes per week of vigorous-intensity aerobic physical activity.

These results are similar to the 15% weight loss noted at 68 weeks with the GLP-1 receptor agonist semaglutide.

My take: GLP-1 receptor agonists help individuals lose weight. However, we’ve seen the promise of medical therapy before so we will have to see how the story ends.

Related blog post: Semaglutide: Potential or Problematic New Treatment for Fatty Liver Disease/NASH

Briefly noted: YY Gibbens et al. American Journal of Gastroenterology 2021 April 22. Effects of Central Obesity on Esophageal Epithelial Barrier Function. Key finding:  Obesity+/GER- group demonstrated increased intercellular space, reduced desmosome density, and increased fluorescein leak compared with control subjects. Thus, obesity may worsen esophageal disease by  impairing the structural and functional integrity of the esophageal barrier independent of GER. (Thanks to Mike Hart for this reference)

FMT Research & The Shawshank Redemption

In The Shawshank Redemption, Andy Dufresne (Tim Robbins) manages to escape prison by crawling through 500 yards of a filthy sewage pipe. It seems like a similar effort will be needed to find out how to benefit from fecal transplantation when given for problems like irritable bowel syndrome and metabolic disease/obesity. Some recent studies and associated editorials are noted below.

T Holvoet et al. Gastroenterol 2021; 160: 145-157. Fecal Microbiota Transplantation Reduces Symptoms in Some Patients With Irritable Bowel Syndrome With Predominant Abdominal Bloating: Short- and Long-term Results From a Placebo-Controlled Randomized Trial

  • Key finding: At week 12, 56% of patients given donor stool reported improvement in both primary endpoints compared with 26% of patients given placebo (P = .03).
  • Commentary: PW O’Toole, F Flanahan. Gastroenterol 2021; 160: 15-17. Full Text: Transplanting Microbes for Irritable Bowels or Irritated Microbes or Both?
    • This editorial stresses that trials of FMT in IBS have had inconsistent results and risks are unclear. “How many clinicians inform patients receiving FMT that the donor microbiota might include components that increase (or decrease) one’s risk of colorectal cancer?” Part of the problem is “due, in part, because a normal microbiome has not been defined.”

E Rinott et al. Gastroenterol 2021; 160: 158-173. Full text Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain

Key findings:

  • In this randomized controlled trial with 90 participants, autologous FMT (aFMT) significantly attenuated weight regain in the green-Mediterranean group (aFMT, 17.1%, vs placebo, 50%; P = .02) and improved insulin resistance: insulin rebound (aFMT, –1.46 ± 3.6 μIU/mL vs placebo, 1.64 ± 4.7 μIU/mL; P = .04) (Graphical abstract below)
  • In mice, Mankai-modulated aFMT in the weight-loss phase compared with control diet aFMT, significantly prevented weight regain and resulted in better glucose tolerance during a high-fat diet–induced regain phase (all, P < .05).

Commentary: M Nieurdorp, K Madsen. Gastroenterol 2021; 160: 17-19. Full text The Promise of Maintaining Diet-Induced Weight Loss by Swallowing One’s Own Feces: Time to Provide a Do-It-Yourself Manual?

  • “These findings add support to the current body of evidence that the gut microbiota have a role in weight gain and metabolism. However, many questions remain. Indeed, although studies have shown varying degrees of effectiveness of FMT in the improvement of metabolic parameters in human participants, there has been no evidence yet that FMT can induce weight loss in obese patients.”
  • “The finding that maintenance of weight loss was only seen in the one dietary group consuming the Mediterranean diet plus green tea and Mankai supplement who received autologous FMT, would suggest that specific microbial profiles may be involved and that weight loss per se may not result in the required microbial profiles.”
Figure 1 from editorial: Challenges associated with the use of fecal microbial transplantation (FMT) as treatment

My take: Both of these studies show that modulation of the fecal microbiome may be helpful under the right set of circumstances to help with both irritable bowel syndrome and metabolic syndrome. However, ‘hundreds of yards’ of more research is needed to determine if this is really feasible and to assure that the benefits outweigh the potential risks.

Related blog posts:

Effects of Fecal Microbiome Transfer in Adolescents With Obesity

KSW Leong et al. JAMA Netw Open. 2020;3(12):e2030415. doi:10.1001/jamanetworkopen.2020.30415 (full text): Effects of Fecal Microbiome Transfer in Adolescents With Obesity Thanks to John Pohl’s twitter feed for this reference.

Methods: Single course of oral encapsulated fecal microbiome from 4 healthy lean donors or saline placebo.

Key findings:

  • In this randomized, double-masked, placebo-controlled trial of 87 adolescents with obesity, FMT alone did not lead to weight loss at 6 weeks.
  • There were no observed effects on insulin sensitivity, liver function, lipid profile, inflammatory markers, blood pressure, total body fat percentage, gut health, and health-related quality of life
  • In post-hoc exploratory analyses among participants with metabolic syndrome at baseline, FMT led to greater resolution of this condition (18 to 4) compared with placebo (13 to 10) by 26 weeks (adjusted odds ratio, 0.06; 95% CI, 0.01-0.45; P = .007)

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Best Studies from Pediatrics

Pediatrics has provided free full publication access to what they consider their best 10 articles and 5 influential COVID-19 publications: Pediatrics2020 Best Articles Link

Here are direct links to 3 of the articles:

O Nafiu et al. Race, Postoperative Complications, and Death in Apparently Healthy Children (Video Abstact available on link) Key finding:

  • Among 172 549 apparently healthy children from a retrospective database, the incidence of 30-day mortality, postoperative complications, and serious adverse events were 0.02%, 13.9%, and 5.7%, respectively. Compared with their white peers, AA children had 3.43 times the odds of dying within 30 days after surgery (odds ratio: 3.43; 95% CI: 1.73–6.79)

K Lycett et al. Body Mass Index From Early to Late Childhood and Cardiometabolic Measurements at 11 to 12 Years. The authors followed 5107 infants from birth. Key findings:

  • At age 6 to 7 years, compared with those with a healthy weight, children with overweight had higher metabolic syndrome risk scores by 0.23 SD units (95% confidence interval 0.05 to 0.41) and with obesity by 0.76 SD units (0.51–1.01), with associations almost doubling by age 10 to 11 years. Thus, overweight and obesity from early childhood onward were strongly associated with higher cardiometabolic risk at 11 to 12 years of age.
  • In addition, obesity but not overweight had slightly higher outcome carotid intima-media thickness (0.20–0.30 SD units) at all ages

A Kempe et al. Parental Hesitancy About Routine Childhood and Influenza Vaccinations: A National Survey Key finding:

  • Hesitancy prevalence was 6.1% for routine childhood and 25.8% for influenza vaccines in this online sample of 2176 parents

How Helpful Are School-Based BMI Measurements?

KA Madsen et al. JAMA Pediatr. Published online November 16, 2020. doi:10.1001/jamapediatrics.2020.4768.Full text link: Effect of School-Based Body Mass Index Reporting in California Public Schools

Methods:  Cluster randomized clinical trial. The Fit Study (2014-2017) randomized 79 California schools (n=28 641 students) to BMI screening and reporting (group 1), BMI screening only (group 2), or control (no BMI screening or reporting [group 3]) in grades 3 to 8. The setting was California elementary and middle school

Key findings:

  • Among 6534 of 16 622 students with a baseline BMI in the 85th percentile or higher (39.3%), BMI reporting had no effect on BMI z score change (−0.003; 95% CI, −0.02 to 0.01 at 1 year and 0.01; 95% CI, −0.02 to 0.03 at 2 years)
  • Weight dissatisfaction increased more among students having BMI screened at school (8694 students in groups 1 and 2) than among control participants (5674 students in group 3).

My take: Tackling obesity will require a lot more than measuring BMIs. An interesting follow-up study would be to see if schools who reported BMIs were more likely to take other measures, such as providing nutritional counseling, improving school lunch selection, and providing opportunity for more activity/exercise.

Related blog posts:

“Leave Overweight Kids Alone”

Aubrey Gordon provides personal insight into the issue of weight stigma in her opinion piece: NY Times Leave Overweight Kids Alone

Here a few excepts:

The war on childhood obesity reached its zenith with the 2010 introduction of the national “Let’s Move!” campaign, “dedicated to solving the problem of obesity within a generation.” It was a campaign against “childhood obesity” — not specific health conditions or the behaviors that may contribute to those health conditions. It wasn’t a campaign against foods with little nutritional value, or against the unchecked poverty that called for such low-cost, shelf-stable foods. It was a campaign against a body type — specifically, children’s body types.

In 2012, Georgia began its Strong4Life campaign aimed at reducing children’s weight and lowering the state’s national ranking: second in childhood obesity. Run by the pediatric hospital Children’s Healthcare of Atlanta, it was inspired in part by a previous anti-meth campaign. Now, instead of targeting addiction in adults, the billboards targeted fatness in children…The billboards purported to warn parents of the danger of childhood fatness, but to many they appeared to be public ridicule of fat kids…

Despite ample federal and state funding, multiple national public health campaigns and a slew of television shows, the war on obesity does not appear to be lowering Americans’ B.M.I.s. According to the Centers for Disease Control and Prevention, since 1999 there has been a 39 percent increase in adult obesity and a 33.1 percent increase in obesity among children.

Weight stigma kick-starts what for many will become lifelong cycles of shame..Yet, despite its demonstrated ineffectiveness, the so-called war on childhood obesity rages on. This holiday season, for the sake of children who are told You’re not beautiful. You’re indulging too much. Your body is wrong. You must have done it, I hope some parents will declare a cease-fire.

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