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.”
Methods: This was a a 72-week, double-blind phase 2 trial involving patients with biopsy-confirmed NASH and liver fibrosis of stage F1, F2, or F3. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or corresponding placebo.
The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo).
An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P=0.48).
The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group.
Safety: Malignant neoplasms were reported in 3 patients who received semaglutide (1%) and in no patients who received placebo. Overall, neoplasms (benign, malignant, or unspecified) were reported in 15% of the patients in the semaglutide groups and in 8% in the placebo group
Clearly this study indicates that there may be safety concerns with semaglutide. In addition to the malignant neoplasms, there were 8 individuals with colonic polyps in the treatment groups and 7 with renal cysts in the treatment group. However, the authors note that in a recent meta-analysis with 55,921 patients, GLP-1 agonists were not associated with an increased risk of malignant neoplasms (Diabetes Obes Metab 2020; 22: 699-704).
Related article: JPH Wilding et al. NEJM 2021; 384: 989-1002. Once-Weekly Semaglutide in Adults with Overweight or ObesityKey finding: The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo. This study indicates potential for GLP-1 Agonist class for pharmacologic treatment of obesity.
My take: The improvement in NASH with semaglutide is encouraging and perhaps improvement in fibrosis will occur with more time. Yet, more time is also needed to determine if this agent is truly safe in this population. In patients receiving other GLP analogues, vigilance for adverse events is needed as well.
A thought-provoking editorial from the NY Times provides a lot of reasons why dieting to lose weight may be counter-productive. This editorial comes right after recent reports that many of the most successful “biggest losers” have regained their weight. Here’s the link. Never Diet Again
Dieting is not successful in adults, with less than 1% achieving long-term success
Our body’s neuroscience has a setpoint for normal weight and when we drop below this, our body deploys a number of mechanisms to regain weight
Dieting may result in long-term weight gain
Dieting may not improve health
Here a few excerpts:
Setpoint: “When dieters’ weight drops below it, they not only burn fewer calories but also produce more hunger-inducing hormones and find eating more rewarding.”
Diet industry: ” A report for members of the industry stated: “In 2002, 231 million Europeans attempted some form of diet. Of these only 1 percent will achieve permanent weight loss.”
Does dieting increase weight gain? “The causal relationship between diets and weight gain can also be tested by studying people with an external motivation to lose weight. Boxers and wrestlers who diet to qualify for their weight classes presumably have no particular genetic predisposition toward obesity. Yet a 2006 study found that elite athletes who competed for Finland in such weight-conscious sports were three times more likely to be obese by age 60 than their peers who competed in other sports.”
Obesity overrated as cause of mortality: “But our culture’s view of obesity as uniquely deadly is mistaken. Low fitness, smoking, high blood pressure, low income and loneliness are all better predictors of early death than obesity. Exercise is especially important: Data from a 2009 study showed that low fitness is responsible for 16 percent to 17 percent of deaths in the United States, while obesity accounts for only 2 percent to 3 percent, once fitness is factored out.”
My take: This short article explains quite well why obesity is so hard to treat with diet approaches. Primary prevention of obesity at younger ages along with emphasis on staying active are likely to achieve more than focusing on diet alone.
A recent study (E Ness-Jensen et al. Clin Gastroenterol Hepatol 2016; 14: 175-82) reviewed the literature and identified 15 original studies which met inclusion criteria regarding lifestyle interventions in gastroesophageal reflux disease (GERD).
Weight loss lowered esophageal acid exposure in 2 RCTs: 5.6% –>3.7% and 8.0%–>5.5% and reduced reflux symptoms in prospective observational studies
Tobacco cessation reduced reflux symptoms in normal-weight individuals in a large prospective cohort study OR 5.67
Head-of-the-bed elevation decreased supine acid exposure from 21% to 15%.
Early evening meals decreased supine acid exposure by 5.2% point change.
My take: With the increasing incidence of obesity, these type of lifestyle modifications need to be implemented in our teenagers with GERD. For those who want to decrease use of medications, these interventions, if emphasized with conviction, are a good first step.
Obeticholic acid, a Farnesoid X Receptor Ligand, is being studied as a potential agent in nonalcoholic steatohepatitis (NASH). According to a recent study (Lancet 2015; 385: 956-65), patients assigned to receive obeticholic acid were more likely to have improved liver histology compared with placebo (50/110 [45%] compared with 23/109 [21%]). The obeticholic group had increase serum cholesterol and LDL cholesterol. This study looked at a subgroup of patients in the FLINT study who had undergone liver biopsies.
E Vilar-Gomez et al. Gastroenterol 2015; 149: 367-78. This prospective study of 293 patients with histologically-proven NASH were followed after undergoing lifestyle changes for 52 weeks. At week 52, 88 subjects (30%) had lost ≥5% of their weight. Degree of weight loss was independently associated with improvements in all NASH-related histologic parameters (steatohepatitis, NAS activity score, and fibrosis.
G Lassailly et al. Gastroenterol 2015; 149: 379-88. Between 1994-2013, 109 morbidly-obese patients with histologically-proven NASH underwent bariatric surgery. One year after surgery, NASH had disappeared from 85% of the patients.
P Angulo et al. Gastroenterol 2015; 149: 389-97. In this retrospective analysis of 619 patients with NAFLD (1979-2005), the authors noted that “fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.”
Design, Setting, and Participants Group-randomized clinical trial conducted during a 16-week period in YMCAs and schools .. Seventy-five overweight or obese children (41 girls [55%], 34 whites [45%], 20 Hispanics [27%], and 17 blacks [23%]) enrolled in a community-based pediatric weight management program. Mean (SD) age of the participants was 10.0 (1.7) years; body mass index (BMI) z score, 2.15 (0.40); and percentage overweight from the median BMI for age and sex, 64.3% (19.9%).
Interventions All participants received a comprehensive family-based pediatric weight management program (JOIN for ME). Participants in the program and active gaming group received hardware consisting of a game console and motion capture device and 1 active game at their second treatment session and a second game in week 9 of the program. Participants in the program-only group were given the hardware and 2 games at the completion of the 16-week program…
Results Participants in the program and active gaming group exhibited significant increases in moderate-to-vigorous (mean [SD], 7.4 [2.7] min/d) and vigorous (2.8 [0.9] min/d) physical activity at week 16 (P < .05). In the program-only group, a decline or no change was observed in the moderate-to-vigorous (mean [SD] net difference, 8.0 [3.8] min/d; P = .04) and vigorous (3.1 [1.3] min/d; P = .02) physical activity. Participants in both groups exhibited significant reductions in percentage overweight and BMI z scores at week 16. However, the program and active gaming group exhibited significantly greater reductions in percentage overweight (mean [SD], −10.9% [1.6%] vs −5.5% [1.5%]; P = .02) and BMI z score (−0.25 [0.03] vs −0.11 [0.03]; P < .001).
Conclusions and Relevance Incorporating active video gaming into an evidence-based pediatric weight management program has positive effects on physical activity and relative weight.
Comment: The costs of the games and game consoles were about $350 according to the authors. Since this was a short study (16-weeks), it is not clear that this will be cost-effective. However, any tools that may help kids become more active are certainly welcome.