Tag Archives: obesity

Should We Be Excited About a New Medication (Liraglutide) for Obesity?

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Thus far, “the benefits of medications to treat obesity remain limited because of side effects and inadequate efficacy, especially in the long term.” This is part of an editorial (Siraj ES, Williams J. NEJM 2015; 373: 82-3) that explains a recent study (Pi-Sunyer X, et al. NEJM 2015; 373: 11-22). However, there is a huge need for a cost-effective medication because bariatric surgery is not feasible for 400 million obese persons worldwide.

Liraglutide (marketed as Victoza) has been approved by the FDA for weight loss in adults based on this published study and two other trials.  Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic.  The authors conducted a 56-week, double-blind trial with 3731 non-diabetic patients. In a 2:1 design, most patients received a once-daily subcutaneous 3.0 mg injection of liraglutide; some received placebo.  Both groups received lifestyle counseling.

Key finding:

  • At week 56, the treatment group had lost a mean of 8.4 kg compared with the placebo group which lost 2.8 kg.

There were similar rates of adverse events (mildly increased in treatment group); the rate of new diagnoses of diabetes was less than one-eighth that in the placebo group.  A 2-year extension trial is being analyzed to further pursue this finding.  Also, the authors note that 4 cases of breast cancer (0.2%) were detected in the treatment group compared with 1 (0.1%) in the placebo group.  This finding could have been due to easier exam following weight loss.  It is noted that the labeling for liraglutide has a black box warning regarding thyroid c-cell tumor risk which have occurred in rodents at clinically relevant doses.

A fairly good 2 minute summary: NEJM Short Take on Liraglutide

Despite the weight loss, the editorial has a cautious tone.

  • “There were statistically significant, although sometimes quantitatively modest, improvements in secondary end points, which included glycemic control, fasting insulin concentrations, cardiometabolic markers, and quality-of-life measures.”
  • “Most obese participants stayed obese, reversal of the metabolic syndrome was not quantified, and liraglutide may be required indefinitely, like statins, but with delivery by injection and at a nontrivial cost.”  According to http://www.goodrx.com, the approximate retail price is $596.01 for 18 mg. For type 2 diabetes, the dosage varies from 1.2 to 1.8 mg per day, after the first week which is dosed at 0.6 mg.

Take-home point: This new medication may help with modest weight loss but at a very significant cost.  In addition, long-term data are lacking. Thus, right now, this medication does not provide the cost-effective option to bariatric surgery.

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Georgia Aquarium

Georgia Aquarium

Helicobacter Pylori: Relationship to Cancer and Dubious Beneficial Claims

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I found a recent review (Gastroenterol 2015; 148: 719-31) regarding Helicobacter pylori (HP) of interest.  David Graham explores the issue of HP eradication with regard to cancer and whether there are benefits to the infection that result in detrimental effects with HP eradication.

The potential mechanisms in which HP infection can increase the risk of gastric cancer are depicted in Figure 2; the most important:

  • Inflammation induced by infection
  • Genetic/epigenetic changes –> genetic instability in gastric epithelial cells

Lessons regarding eradication therapy:

  • Sequential therapy has been shown in some studies to be effective/superior (in Italy) yet inferior in others (eg. Korea).  “The results are explained entirely by differences in patterns of drug resistance, which typically were not assessed before studies were initiated.”
  • Findings from many studies cannot be applied to other populations without resistance data.

Does HP infection reduce the risk of obesity or childhood asthma?  Probably not.

  • “Any claim that a major human pathogen also might provide a meaningful health benefit, and that plans to eradicate it should be reconsidered, is guaranteed to elicit interest from the press.”
  • As a counter example, Dr. Graham notes “because 2 events are associated does not mean that one causes the other. For example, one study reported a correlation between the number of storks in Brandenburg, Germany, and the birth rate in Berlin.” [Backen MB. Harm. In: Bracken MB. Risk, chance, and causation. New Haven: Yale University Press, 2013; 108-09.]
  • He notes that HP can both promote or inhibit acid secretion/acid reflux.  Increased acid secretion with resultant esophageal disease could increase the risk of adenocarcinoma of the esophagus; however, “the risk of developing adenocarcinoma of the stomach remains higher than the risk of adenocarcinoma of the esophagus.”  This indicates that if there is an increased esophageal cancer risk, eradication would still be favorable by lowering gastric cancer risk.
  • Asthma: “overall, the studies do not support the hypotheses that increases in childhood asthma were related to the absence of H pylori.”
  • Obesity: “A meaningful causative association between H pylori and obesity is unlikely.”
Screen Shot

Screen Shot

Take-home message: H pylori is a pathogen and should be treated as such.

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University of Chicago

University of Chicago

Reaching Consensus on Bariatric Intervention in Children and Adolescents

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A recent medical position paper (Nobili V, et al. JPGN 2015; 60: 550-61) provides guidance for bariatric surgery intervention in children and adolescents with and without nonalcoholic fatty liver disease (NAFLD).

While the authors acknowledge that bariatric surgery can “dramatically reduce the risk of adulthood obesity and obesity-related diseases,” they advocate its use in adolescents with the following:

  • BMI >40 kg/m-squared with severe comorbidities: type 2 diabetes mellitus, moderate-to-severe sleep apnea, pseudotumor cerebri, or NASH with advanced fibrosis (ISHAK score >1)
  • BMI >50 kg/m-squared with mild comorbidities: hypertension, dyslipidemia, psychological distress, gastroesophageal reflux, anthropathies, NASH, impairment in activities of daily living, mild obstructive sleep apnea, panniculitis, chronic venous insufficiency, urinary incontinence
  • Additional criteria: have attained 95% of adult stature, failed behavioral/medical treatments, psychological evaluation perioperatively, avoid pregnancy for 1 year after surgery, will adhere to nutritional guidelines after surgery, informed assent from teenager (along with parental consent)

Key points:

  • “There is a lack of randomized controlled trials examining the effects of bariatric surgery on NAFLD or NASH.”  In Table 3, the authors provide a summary of 16 previous studies/outcomes; though none of the studies enrolled more than 60 patients.
  • In an adult prospective study with 381 patients (Mathurin P et al. Gastroenterol 2009; 137: 532-40), there was a significant decline in the severity/prevalence of steatosis and resolution of NASH at 1 and 5 years.
  • Bariatric surgery, in adult studies, have improved diabetes, insulin resistance, hypertension, and dyslipidemia.
  • Patients who have “undergone bariatric surgery show higher suicide rates than the general population.”  Psychological evaluation should be integrated with surgical decision.
  • Type of surgery: Roux-en-Y Gastric Bypass (RYGB) is favored by the authors; they also discuss studies with Laparoscopic Adjustable Gastric Banding (LAGB).  “RYGB and LAGB are the 2 main surgical procedures that have been used in pediatric obesity.  RYGB is considered a safe and effective option for adolescents with extreme obesity, as long as appropriate long-term follow-up is provided. LAGB has not been approved by Food and Drug Administration for use in adolescents, and there should be considered investigational only.”

It is interesting that the authors are so deferential to the Food and Drug Administration.  It is clear from their position paper that LAGB has similar evidence supporting its use in adolescents as RYGB.  They even note that it has potential for reversibility and “an excellent safety profile with a lower risk of postoperative vitamin deficiencies when compared with biliopancreatic diversion and RYGB.”

Bottomline: Given the continuation of the obesity epidemic, additional pediatric medical expertise will be needed to help evaluate adolescents for bariatric surgery and to follow them postoperatively.

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Do You Think Fruit Drinks Are Healthy?

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According to a recent report in USA Today, a large number of parents have been misled into thinking that sugary beverages and fruit drinks are healthy. Here’s an excerpt:

That’s the conclusion of a new study from the Rudd Center for Food Policy and Obesity at University of Connecticut, published today in Public Health Nutrition.

Many parents believe that drinks with high amounts of added sugar — particularly fruit drinks, sports drinks and flavored water — are “healthy” options for kids, according to the report, funded by the Robert Wood Johnson Foundation, which focuses on improving health and health care…

The vast majority of parents give kids sugary drinks regularly…Equally significant, nearly half of parents surveyed rated flavored waters as healthy, and more than one-quarter considered fruit drinks and sports drinks to be healthy…

Parents said they were particularly influenced by nutritional claims appearing on the packages — such as claims that the items are “real” or “natural” or contained vitamin C or antioxidants, or were low in sodium or calories.

Bottomline: This information reinforces the fact that many parents do not realize basic nutrition information.

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In NASH, is ALT Wrongly Used as a Marker of Liver Injury?

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According to a recent report (Hepatology 2015; 61: 153-60), elevation of alanine aminotransferase (ALT) which is frequently used as an indicator to select patients for further investigations (eg. liver biopsy) is NOT a good indicator of liver parenchymal injury in patients with nonalcoholic fatty liver disease (NAFLD).

The researchers enrolled 440 patients and divided them into three groups: no NAFLD (n=60), NALFLD with normal ALT (n=165), and NAFLD with elevated ALT (n=215). The patients were overweight/obese patients prospectively recruited from newspaper ads, general medicine clinics and hepatology clinics at several VA hospitals. Those with history of alcohol abuse were excluded.

Numerous investigations were performed including liver fat by proton magnetic resonance spectroscopy (H-MRS), liver biopsy (n=293), and insulin resistance measurements.

Key findings:

  • NAFLD & NASH patients with elevated ALT had higher liver triglyceride content (P<0.0001), worse adipose tissue insulin resistance (ATIR) (P<0.0001), and lower plasma adiponectin (P<0.05).
  • Steatosis was worse on liver biopsy in those with NASH and elevated ALT (P<0.0001).
  • There were no differences in liver inflammation (P=0.62), ballooning (P=0.13), or fibrosis (P=0.12). Thus, patients with normal versus elevated ALT had similar severity of NASH liver histology.

Take-home message:  In adults, ALT values are “poor surrogate markers of disease activity” in NAFLD.  ALT values, in these patients, are indicative of metabolic disease.  Given the staggering numbers of individuals, adults and children, with fatty liver disease, the lack of simple screen tool is quite problematic.  Equally problematic is a lack of a simple treatment approach.

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Dropping Weight by Adding Fiber in Diet

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A recent study showed that increasing fiber in the diet helped participants lose weight.  The details are noted in this LA Times story: To lose weight, experts suggest a focus on fiber

Here’s an excerpt:

If you’re trying to lose weight, you could count your calories, keep track of precisely how much salt and sugar your eat, and make sure you hit certain targets for protein, carbohydrates, cholesterol and the various types of fat. Or you could set all of that aside and concentrate on just one thing: Eating at least 30 grams of fiber each day.

In a yearlong clinical trial involving 240 obese people who had metabolic syndrome, those who focused on fiber lost almost as much weight as those who followed the American Heart Assn.’s extremely detailed dietary recommendations.

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Some funny headlines form Freakomomics website –here’s one:

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Family Meals –Protection Against Obesity?

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According to a 10-year longitudinal study, increased family meal frequency during adolescence was associated with a reduced odds of overweight or obesity (Berge JM et al, J Pediatr 2015; 166: 296-301, editorial 220-21).

The data from this study derived from Project EAT I and EAT III which examined at baseline middle school and high school students at 31 public schools in Minnesota.  Ultimately the participants (n=2117) were followed over 10 years.

Key finding:

  • “Results showed that eating family meals together, ranging from 1-2 to 5 or more times during 1 week, was significantly predictive of lower odds of being overweight or obese 10 years later.”  This effect was largest among African American participants.
  • Odds ratios for overweight/obesity was similar with any frequency of family meals compared to no family meals: 1-2 times/week OR 0.67, 3-4 times/week OR 0.50, and 5 or more/week OR 0.68

Why does this occur?

There is not an answer to this question.

Speculation from the authors:

  • “Healthier meals”
  • “Opportunities for emotional connection”
  • “Parental modeling”

In my view, family meals may be an epiphenomenon.  It may be a marker for a more organized household which is likely to have some favorable effects.

Bottomline: Another reason to eat together.  Besides having a chance to catch up on your kids, it may keep them healthier.

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Leptin Deficiency and Early-Onset Extreme Obesity

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A brief report (NEJM 2015; 372: 48-54) details a case of 2.5 year old who weighed 33.7 kg (>99.9% and z score of 7.2) and had BMI of 38.6 (>99.9% and z score of 5.8).

Link to article (and picture/growth curve)

The authors determined that he had a mutation which caused biologically inactive leptin.  Subsequently, treatment with metreleptin injections, improved eating behavior and resulted in substantial weight loss.

Key points:

  • “Current clinical recommendations advise that leptin serum concentrations be measured in children who have rapid weight gain in the first months of life.” (“The severely obese patient –a genetic work-up.” Nat Clin Pract Endocrinol Metab 2006; 2: 172-7)
  • This case report demonstrates that normal circulating levels of the hormone “do not rule out disease-causing mutations in the gene encoding leptin.”

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Heavy Heart due to Obesity

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A recent study (J Pediatr 2014; 165: 1184-9) documents a “cardiometabolic phenotype” which indicates that obesity and metabolic disease exert effects at a young age.

Design: A cohort of 281 white children from Italy were carefully studied with antropometrics, lipids profiles, blood pressure, glucose, and echocardiography. Of these children, 105 were obese (mean age 11 years) and 105 were morbidly obese (mean age 12 years); 31 had normal weight and 40 were overweight.

Key findings:

  • Heart disease: 53 had eccentric left ventricular hypertrophy (LVH), 36 had concentric LV remodeling, 44 had concentric LVH, 148 had normal echocardiograms.
  • Children with concentric LVH exhibited the most severe metabolic disturbances (graphically demonstrated in Figure 1)

Bottomline: The authors conclude that “we have identified a “cardiometabolic phenotype” occurring early in life, characterized by concentric LVH, visceral obesity, high BP, high Tg/HDL-C, and high-normal FPG [fasting plasma glucose].  This result may be clinically relevant because, in adulthood, a concentric LV geometric pattern is associated with a greater risk of CV events.”

Yosemite

Yosemite

Could Obesity Be Cured/Created at Birth with Manipulation of Microbiome?

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A concise review (NJEM 2014; 371: 2526-28) quickly describes the latest science on microbiota, antibiotics, and obesity chiefly by summarizing the work of Cox LM et al (Cell 2014; 158: 705-21).

Key points:

  • In mice, studies have shown that low-dose penicillin in early life induces marked effects on body composition (eg. excessive weight gain) lasting into adulthood
  • Prenatally administered penicillin to the mother and high-fat diet also induced fat mass of male mice.
  • Gut microbiota transferred from penicillin-moderated flora mice (at 18 weeks) into the cecums of 3-week-old germ-free mice also resulted in excessive fat mass compared to controls who received gut microbiota transfer from control mice (who did not receive penicillin).
  • “These results suggest that immunologic and metabolic changes are not caused by direct effects of antibiotics but rather by derived changes in the gut microbiota.”
  • “It may even be speculated that in families in which obesity is a problem, specific antibiotic treatment at birth could reverse the adverse effect of obesogenic microbiota transferred from mother to infant during delivery.”

Take-home message: Understanding the microbes in our bodies may lead to much more than curing intestinal infections and intestinal maladies.

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