Semaglutide in Adolescent Obesity

D Weghuber et al NEJM 2022; DOI: 10.1056/NEJMoa2208601. Once-Weekly Semaglutide in Adolescents with Obesity

Methods: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled 201 adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition.  180 (90%) completed treatment. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention.

Key findings:

  • The mean change in BMI from baseline to week 68 was −16.1% with semaglutide and 0.6% with placebo
  • At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group
  • Improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo
  • “The safety of semaglutide in this adolescent population appeared to be consistent with findings among adults with overweight or obesity… Gastrointestinal disorders (primarily nausea, vomiting, and diarrhea) were the most frequent adverse events with semaglutide (occurring in 62% of participants, as compared with 42% in the placebo group) and were generally mild or moderate in severity and of short duration (median duration, 2 to 3 days for nausea, vomiting, and diarrhea in the semaglutide group)”
  • “Permanent discontinuations because of gastrointestinal disorders were very low. Furthermore, semaglutide did not appear to affect growth or pubertal development during the trial period”

My take: As in adults, treatment with semaglutide results in weight loss.

Related blog posts:

AGA Guidelines for Adults with Obesity

AGA released new evidence-based guidelines strongly recommending patients with obesity use recently approved medications paired with lifestyle changes.

The following medications, paired with healthy eating and regular physical activity, are first-line medical options and result in moderate weight loss as noted as a percentage of body weight (reported as the difference compared to percent weight loss observed in the placebo group).

  1. Semaglutide (Wegovy®), weight loss percentage: 10.8%
  2. Phentermine-topiramate ER (Qsymia®), weight loss percentage: 8.5%
  3. Liraglutide (Saxenda®), weight loss percentage: 4.8%
  4. Naltrexone-Bupropion ER (Contrave®), weight loss percentage: 3.0%

Read the AGA Clinical Guidelines on Pharmacological Interventions for Adults with Obesity for the complete recommendations.

Tirzepatide: Promotes Impressive Weight loss

Source Study: AM Jastreboff et al NEJM 2022; DOI: 10.1056/NEJMoa2206038. Tirzepatide Once Weekly for the Treatment of Obesity

USA Today (6/6/22): Diabetes drug helps patients lose never-before-seen amounts of weight, study shows

An excerpt:

The drug, called tirzepatide, works on two naturally occurring hormones that help control blood sugar and are involved in sending fullness signals from the gut to the brain...Those taking the highest of three studied doses lost as much as 21% of their body weight – 50-60 pounds in some cases…

Another obesity treatment approved last year called semaglutide, from Novo Nordisk, provides an average of up to about 15% weight loss. Previous generations of diet drugs cut only about 5% of weight and many carried prohibitive side effects…

About 15% of participants who received the active drug dropped out of the 72-week trial, about a third because of gastrointestinal side effects. Twenty-six percent of trial volunteers who received a placebo dropped out.

On May 13, the Food and Drug Administration approved tirzepatide, under the trade name Mounjaro, for the treatment of Type 2 diabetes…The new tirzepatide trial, called SURMOUNT-1, included more than 2,500 volunteers [without diabetes]…Nine out of 10 lost weight, and on the highest dose, 15 mg, they lost an average of 52 pounds each...

It’s too soon to know what price Lilly will set for tirzepatide. Mounjaro, the same drug used to treat diabetes at the same doses, retails for almost $1,000 a month…Semaglutide went on the market last year for weight loss and has been in short supply ever since, Rind said. It costs about $1,600 a month for the 2.4 mg weight loss dose, which is higher than the 1 or 2 mg doses used to treat diabetes. Like other weight loss drugs, semaglutide isn’t covered by many insurance plans. 

My take: This therapy, already approved for Type 2 Diabetes, appears promising for obesity but costly. More time will be needed to understand the safety profile with extended use.

Related blog post: Are We On the Verge of Pharmacologic Management of Obesity (Again)?

Atalaya Hike, Santa Fe, NM

Does Motivational Interviewing Help Long-Term Outcomes for Obesity?

M Michalopoulou et al. Annals Int Med 2022; https://doi.org/10.7326/M21-3128. Effectiveness of Motivational Interviewing in Managing Overweight and Obesity

This review and meta-analysis examined forty-six studies involving 11 077 participants.

Key findings:

  • At 6 months, behavior weight management programs (BWMPs) using motivational interviewing (MI) were more effective than no/minimal intervention (−0.88) but were not statistically significantly more effective than lower-intensity (−0.88 ) or similar-intensity (−1.36 ) BWMPs.
  • “At 1 year, data were too sparse to pool comparisons with no/minimal intervention, but MI did not produce statistically significantly greater weight change compared with lower-intensity”

My take: Several years ago our hospital system strongly encouraged practitioners to learn motivation interviewing techniques. However, based on this review, “there is no evidence that MI increases effectiveness of BWMPs in controlling weight.”

Related blog posts:

Isle of Palms, SC

Timing of Solids and Weight Trajectory

CJ D’Hollander et al. J Pediatr 2022; 240: 102-109. Timing of Introduction to Solid Food, Growth, and Nutrition Risk in Later Childhood

Methods: A longitudinal cohort study was conducted among healthy children 0-10 years of age participating in The Applied Research Group for Kids study between June 2008 and August 2019 in Toronto, Canada.

Key findings:

  • Of 8943 children included, the mean (SD) age of infant cereal introduction was 5.7 (2.1) months
  • Children who were introduced to infant cereal at 4 vs 6 months had 0.17 greater body mass index z score (95% CI 0.06-0.28; P = .002) and greater odds of obesity (OR 1.82; 95% CI 1.18-2.80; P = .006) at 10 years of age. 
  • Earlier cereal introduction was associated with a less-favorable eating behavior score at 18 months to 5 years of age (0.18 units higher; 95% CI 0.07-0.29; P = .001).

Limitation: This study did not randomize children into early vs late cereal introduction; thus, there may be unidentified confounders that contribute to weight gain in children offered cereal at a younger age.

My take: This study indicates that introduction of cereal at 6 months of age, rather than 4 months of age, may be beneficial in limiting excess weight gain.

What’s More Important for Health: Exercise or Weight loss?

GA Gaesser, SS Angadi. iScience 2021; https://doi.org/10.1016/j.isci.2021.102995. Open access: Obesity treatment: Weight loss versus increasing fitness and physical activity for reducing health risks

Key points from this review of more than 200 relevant meta-analyses and individual studies:

  • “A weight-neutral approach to treating obesity-related health conditions may be as, or more, effective than a weight-loss-centered approach, and could avoid pitfalls associated with repeated weight loss failure… Epidemiological studies show that CRF (cardiorespiratory fitness) and PA (physical activity) significantly attenuate, and sometimes eliminate, the increased mortality risk associated with obesity. More importantly, increasing PA or CRF is consistently associated with greater reduction in risk of all-cause and CVD mortality than intentional weight loss.”
  • “The increased prevalence of weight loss attempts in the United States has coincided with the increased prevalence of obesity. Thus, a weight-centric approach to obesity treatment and prevention has been largely ineffective. It is unlikely that continued focus on weight loss as the primary metric for success will reverse the trends in obesity prevalence or result in sustainable weight loss. In fact, chronic weight cycling is the norm for millions of adults and is likely to remain so for as long as weight loss persists as the cornerstone of obesity treatment. Weight cycling is associated with health risks that are very similar to those associated with obesity, including higher all-cause mortality risk, and may contribute to weight gain.”

NY Times (9/29/21): Why Exercise Is More Important Than Weight Loss for a Longer Life “People typically lower their risks of heart disease and premature death far more by gaining fitness than by dropping weight.”

Related blog posts:

Figure 2 from article: “Joint associations between cardiorespiratory fitness (CRF), body mass index (BMI), and all-cause (top) and cardiovascular disease (CVD) (bottom) mortality. Hazard ratios reflect the pooled data from the meta-analyses of Barry et al. for all-cause mortality (Barry et al., 2014) and cardiovascular disease mortality (Barry et al., 2018). For all-cause mortality, the meta-analysis included 6 cohorts of men only, 2 cohorts of women only, and 2 cohorts of both men (~80%) and women. For CVD mortality,
the meta-analysis included 8 cohorts of men only and 1 cohort of both men (89%) and women”

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.

Related blog posts:

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: