Tag Archives: obesity

Two new drugs for obesity

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Undoubtedly, a safe, effective medication for obesity would be a pharmaceutical blockbuster.  The record so far on previous medications has been dismal.  Many have been abandoned due to safety concerns, including sibutramine (myocardial infarction and stroke) as well as dexfenfluramine/fenfluramine (valvulopathy).  Two new FDA-approved agents have shown promise but caution in their use will be needed (NEJM 2012; 367: 1577-79).  Neither agent has approval for pediatric usage.

Belviq (lorcaserin) is a selective agonist of the serotonin 5-HT-2C receptor and Qsymia (phentermine with topiramate) is a combination sympathomimetic amine (anorectic agent) with an antiepileptic drug.

In studies with lorcaserin, three studies (1-year placebo-controlled) have shown that the number of patients losing >5% of body weight was increased compared to placebo.  Mean percentage body weight loss with lorcaserin was -5.8% in first two studies and -4.5% in third study.  In contrast, placebo patients who received lifestyle counseling lost  -2.5% and -1.5% respectively.  Overall, up to 47% of patients receiving medication lost more than 5% body weight.

Potential safety concerns with lorcaserin:  initially there were concerns due to increased incidence of tumors in rats and possible valvulopathy (eg. mitral or aortic valve regurgitation).  However, the FDA has concluded that it is unlikely that these are likely to occur in humans.

With phentermine/topiramate, two placebo-controlled studies have shown an increase in patients losing >5% of body weight compared to placebo.  In the first study, the mean percentage change in body weight was -10.9% combination (dosage 15 mg/92 mg) compared with -1.6% for placebo.  In the second study, this dosage led to a -9.8% reduction compared with -1.2% in placebo patients. Overall, up to 70% of patients receiving medication lost more than 5% body weight.

With regard to safety, it is known that topiramate is teratogenic and increases the risk of orofacial cleft.  Due to this, approval for this combination requires a risk evaluation and mitigation strategy (REMS) which permits only specially-certified pharmacies to dispense along with formal training for prescribers. In addition, this combination has been associated with mildly increased heart rate. Due to favorable changes in blood pressure, the FDA concluded that this medication had a good benefit-risk balance.  But, the manufacturer recommends against it use in patients with cardiac issues or cerebrovascular disease.

With both new medications, other safety concerns include the risk of increased psychiatric effects.  In addition, specific recommendations include the following:

  • Only recommended in adults with BMI ≥30 or adults with BMI ≥27 with at least one weight-related comorbidity
  • With both medications, if weight loss not adequate after 12 weeks then discontinue medication.  With lorcaserin, if weight loss is not ≥5%, then discontinue.  With phentermine/topiramate, if weight loss is not ≥3% at 12 weeks (with 7.5 mg/46 mg), consider dosage increase and/or discontinuation.

Related blog entries:

Preventing Type 2 Diabetes

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A ‘perspective’ article reviews data from several studies that show the efficacy of medical treatments aimed at preventing type 2 diabetes (NEJM 2012; 367: 1177-79).

The Diabetes Prevention Program (DPP) was a comparative effectiveness trial of 3234 overweight or obese adults with impaired glucose tolerance (prediabetes).  Findings from this study (published in 2002) showed that lifestyle intervention (attempts at weight loss through diet and exercise) reduced conversion to diabetes by 58% over 3 years, whereas metformin reduced this conversion by 31% over 2 years.  Lifestyle intervention worked best in patients ≥ 60 years.

Subsequently, 88% of these subjects were enrolled in the 10-year outcome study (DPPOS).  The lifestyle intervention group had a 31% 10-year reduction in diabetes compared with 18% for metformin.

The editorial points out that there have been efforts to expand these results across the country through CDC-sponsored programs in cooperation with the YMCA and UnitedHealth.

Potential roadblocks remain:

  • Most payers do not cover these preventive services.
  • US Preventive Services Task Force (USPSTF) has not issued a recommendation on these services.  this affects both public and private insurance coverage.
  • Metformin which may be useful in younger populations does not have a specific indication for diabetes prevention from the FDA (off-label use only).

Whether prevention is ‘worth a pound of cure’ may be hard to discern with prediabetes.    Since the peak incidence of diabetes is between 50 and 60 years and complications often emerge more than a decade later, the benefits of preventing diabetes may not be fully apparent for quite a long time.

Related blog entries:

Treating diabetes with surgery | gutsandgrowth

Lower leptin with physical activity | gutsandgrowth

Staggering cost of obesity | gutsandgrowth

Eliminating sweetened beverages to help obesity

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For every difficult problem there’s a solution that’s simple, neat and wrong.–HL Mencken

Two studies from the New England Journal of Medicine, thus far (at the time of writing) published only online, shed some light on the difficult problem of consumption of sugar-sweetened beverages and its relationship to obesity:

  • A Trial of Sugar-free or Sugar-Sweetened Beverages and Body Weight in Children. Janne C. de Ruyter, M.Sc., et al. September 21, 2012DOI:  10.1056/NEJMoa1203034

  • A Randomized Trial of Sugar-Sweetened Beverages and Adolescent Body Weight. Cara B. Ebbeling, Ph.D., et al,  September 21, 2012DOI:  10.1056/NEJMoa1203388

The first study was an 18-month double-blind, randomized, controlled trial with 641 primarily normal-weight children between 4-12 years of age; patients were recruited from elementary schools.  Patients either received a sugar-free artificially sweetened beverage or a similar sugar-containing beverage, 8 oz per day at school.  At 18 months, 74% continued consuming these beverages; among those remaining in the program, on average, they consumed 83% of the assigned 7 cans each week.  Another marker of adherence was increased urinary sucralose in the sugar-free group (6.7 mg/L compared with 0.1 mg/L in the sugar group). Weight gain was less in the sugar-free group: 6.35 kg compared with 7.37 kg.  Other measures of weight gain were less as well, including skinfold-thickness, waist-to-height ratio, and fat mass. It is also noted that in the U.S. the average consumption of sweetened beverages is three times the amount noted in this Dutch study.

The second study examined 224 overweight and obese adolescents who were randomly assigned into experimental and control groups.  The experimental group received a 1-year intervention designed to decrease consumption of sugar-sweetened beverages; they were followed for an additional year afterwards.  Retention rates were good: 93% at 2 years. To support the experimental group, sugar-free beverages were delivered to  the house and the families received monthly motivational calls. In addition, patients had three check-in visits and written materials. The consumption of sugar-sweetened beverages declined in the experimental group from a baseline of 1.7 servings per day to nearly 0 at 1 year & remained lower at 2 years than the control group.  The primary outcome, BMI, did not differ significantly between the two groups at 2 years nor did change in body fat percentage.  (BMI did improve at 1 year, -0.57.)  In the small number of Hispanic participants (n=27 in experimental group), there was a significant change in BMI at both 1 and 2 years.

While consumption of sugar-sweetened beverages have been considered to be more fattening than solid foods because they do not lead to a sense of satiety, it appears that restriction of these beverages by itself will not make a major dent in the problem of obesity.

Related blog posts:

NAFLD Guidelines 2012

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Psychology of obesity and food addiction

Weight of the Nation

Cardiovascular disease for the entire family

TODAY is worrisome for a lot of tomorrows

A double whammy –obesity and GERD

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“A double whammy is when something causes two problems at the same time, or when two setbacks occur at the same time.”  Double whammy – Idiom Definition – UsingEnglish.com

Obesity probably doesn’t fit this definition strictly because it causes a lot more than two setbacks.  However, obesity clearly causes its own set of problems and, even in childhood, contributes to the development of gastroesophageal reflux disease (GERD) (JPGN 2012; 55: 72-75).

This study consisted of 153 healthy children from a well-child clinic; among this group 31 were obese and 122 were nonobese.  All caregivers completed a reflux questionnaire.  The reflux symptomatic score was significantly higher in children with waist circumference (WC) >90th percentile compared with those <75th percentile.  Furthermore, the rise in GERD symptoms (heartburn, epigastric pain, and regurgitation) was shown to rise progressively with increasing BMI and WC.

One of the shortcomings of the study was the use of a questionnaire that has not been validated for assessment of reflux symptoms in children (according to the authors, none are available in children); though, this questionnaire has been used in a few prior publications.

More references on GERD and obesity:

  • -Gastroenterology 2010; 139: 1902, 1823.. Abdominal visceral adipose tissue increases risk for Erosive esophagitis.
  • -Ann Intern Med 2005; 143: 199-211. Pooled studies showed GERD symptoms with ORs of 1.43 c BMI 25-30 & 1.94 for > 30. OR for esophagitis was 1.76 for BMI>25 & increased risk of adenoca of 1.68-2.02
  • -Gastroenterology 2006; 130: 1925-6.  Obese youth have more reflux symptoms as with adults.

Previous post on GERD and asthma:

Treating reflux does not help asthma

Weight of the Nation

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A perspective article, NEJM 2012; 367: 389-391, addresses the topic of whether Americans are ready to solve the problem of obesity.  Short answer: No!

The article discusses the Institute of Medicine (IOM) report “Accelerating Progress in Obesity Prevention: Solving the Weight of the Nation” along with the accompanying HBO documentary (HBO: The Weight of the Nation).

“The centerpiece of THE WEIGHT OF THE NATION campaign is the four-part documentary series, each featuring case studies, interviews with our nation’s leading experts, and individuals and their families struggling with obesity. The first film, CONSEQUENCES, examines the scope of the obesity epidemic and explores the serious health consequences of being overweight or obese. The second, CHOICES, offers viewers the skinny on fat, revealing what science has shown about how to lose weight, maintain weight loss and prevent weight gain. The third, CHILDREN IN CRISIS, documents the damage obesity is doing to our nation’s children. Through individual stories, this film describes how the strong forces at work in our society are causing children to consume too many calories and expend too little energy; tackling subjects from school lunches to the decline of physical education, the demise of school recess and the marketing of unhealthy food to children. The fourth film, CHALLENGES, examines the major driving forces causing the obesity epidemic, including agriculture, economics, evolutionary biology, food marketing, racial and socioeconomic disparities, physical inactivity, American food culture, and the strong influence of the food and beverage industry.”

While the IOM report identifies a need for structural changes in our environment, public opinion consistently focuses on personal responsibility.

  • 64% identify overeating, lack of exercise, and watching too much TV as the biggest causes
  • 18% identify external factors as the biggest causes, including exposure to junk food, lack of safe places to play, limited availability of healthy foods

Obstacles for addressing this problem also include the following:

  • Obesity-prevention efforts may further stigmatize individuals. The article specifically cites criticism aimed at ‘ads that aired in Georgia;’ these were pulled after concerns of increasing obesity stigma.
  • “Issue-attention cycle” problem.  “This pattern occurs when initial public alarm over the discovery of a problem and optimism about its quick resolution are replaced by the realization that solving the problem will require some public sacrifice and will displace powerful societal interests.”

Related blog posts:

Is obesity neglect?

NAFLD Guidelines 2012

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Is obesity neglect?

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Usually not –according to a thoughtful commentary on this controversial topic (J Pediatr 2012; 160: 898-99).

Suggested criteria for child removal:

  • 1. High likelihood for serious and imminent harm
  • 2. Reasonable likelihood that coercive intervention will be effective
  • 3. Absence of alternative options for addressing the problem

However, “allowing a child to lose all opportunity to live into healthy adulthood when effective treatment is available runs contrary to the central mission of child rearing…When this occurs, regardless of the cause, it must be all about the child, and something must be done.”

Related blog posts:

Treating diabetes with surgery

Lower leptin with physical activity

Staggering cost of obesity

Additional references:

NAFLD Guidelines 2012

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Given the pervasiveness of Non-alcoholic Fatty Liver Disease (NAFLD), updated practice guidelines are worth a look (Hepatology 2012; 55: 2005-23, also in Gastroenterology 2012; 142: 1592-1609)).  While the review includes updated information on incidence, prevalence, risk groups, natural history, the focus remains on specific graded recommendations.

These AGA/AASLD/ACG guidelines do not recommend screening adults due to uncertainties surrounding diagnostic tests and treatment.  This includes high risk populations such as diabetics and bariatric patients.  In addition, unlike recent obesity guidelines from the AAP (Pediatrics 2007; 120: S164-192), these guidelines do not recommend screening children for NAFLD.

Specific management recommendations:

  • Exclude competing etiologies in patients with suspected NAFLD: iron studies, autoantibodies, Wilson’s, viral hepatitis, celiac serology, muscle disease
  • Consider liver biopsy in higher risk patients: metabolic syndrome patients, patients with higher NAFLD Fibrosis score, or before treatment
  • Serum/plasma CK18 is promising biomarker.  Not recommended for routine practice at this time.

Treatment Recommendations:

  • Weight loss (3-5%) helps steatosis and greater losses (up to 10%) may be needed to improve necroinflammation.
  • Metformin –not recommended for liver disease in NASH/NAFLD.
  • Pioglitazone can be used to treat steatohepatitis; however, “long-term safety and efficacy of pioglitazone in patients with NASH is not established.”
  • Vitamin E at 800 units/day improves liver histology in biopsy-proven NASH.  Not recommended without biopsy-confirmed NASH, in diabetic patients, or patients with cirrhosis.  Concern with Vitamin E in adults has been an association with increased all-cause mortality in some studies (but not in others).
  • Avoid alcohol in patients with NAFLD

Website to download PDF version:

http://www.gastro.org/journals-publications/news/societies-develop-new-nafld-clinical-practice-guideline

Another opinion on which patients to biopsy:

http://www.gastro.org/journals-publications/aga-perspectives/june-july-2012/should-we-routinely-do-liver-biopsy-in-nafld-patients

Related posts:

A liver disease tsunami

TODAY is worrisome for a lot of tomorrows

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The TODAY study (NEJM 2012; 366: 2247-56 and editorial 2315-16) =Treatment Options for Type 2 Diabetes in Adolescents and Youth.

While the study has a catchy acronym, the findings are disturbing.  Eligible patients (n=699) were 10 to 17 years old were followed on average over 3.86 years; they were divided into three groups:

  • Metformin 1000mg BID –48% achieved primary outcome (glycated hemoglobin <8% for at least 6 months).
  • Metformin with lifestyle changes –53% achieved primary outcome.  The lifestyle counseling that patients received in the study likely exceeded the typical counseling that most patients receive in clinical practice.
  • Metformin with rosiglitazone (4mg BID) –61% achieved primary outcome.  While this group had the best glycemic response, this group also had the greatest increase in BMI.

Other findings:

Comorbid conditions were common:

  • Hypertension: at baseline in 81 (11.6%) and new cases during study 155 (22.2%)
  • Dyslipidemia (LDL): at baseline in 23 (3.3%) and new cases during study 49 (7%)
  • Triglyceridemia: at baseline in 127 (18.2%) and new cases during study 70 (10%)
  • Microalbuminurina: at baseline in 44 (6.3%) and new cases during study 72 (10.3%)

Frequent adverse events noted with medications (Table 2 in study): gastrointestinal symptoms noted in about half of all study participants in each group, rash noted in about 40%, and elevated LFTs in about 40%.

Take home messages (borrowed from editorial):

“Most youth with type 2 diabetes will require multiple oral agents or insulin therapy within a few years after diagnosis”

“Fifty years ago, children did not avoid obesity by making healthy choices; they simply lived in an environment that provided fewer calories and included more physical activity.”

“Public-policy approaches–sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement…will be necessary to stem the epidemic of type 2 diabetes and its associated morbidity.”

Related posts:

Treating diabetes with surgery

Cardiovascular disease for the entire family

Staggering cost of obesity

Lower leptin with physical activity

Treating diabetes with surgery

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Two articles in the New England Journal of Medicine point to the role of bariatric surgery in  treating type 2 diabetes in obese patients (NEJM 2012; 366: 1567-76 & 1577-85).  Type 2 diabetes looms as one of “the most challenging contemporary threats to public health.”

The first study was a randomized nonblinded single-center trial with 150 patients; mean BMI 36 with 34% having a BMI less than 35.  Intensive medical therapy was compared to Roux-en-Y gastric bypass or sleeve gastrectomy.  Mean patient age was 49 years. 42% of the gastric bypass group, 37% of the sleeve-gastrectomy group, and 12% of the medical treatment group achieved the primary end-point of a glycated hemoglobin level of ≤6% by the 12 month followup; the average starting glycated (HgbA1C) hemoglobin was 9.2%.  At the conclusion of the study, the average HgbA1C was 6.4, 6.6, and 7.5 respectively in the three groups.

The second study used a similar trial with 60 obese patients; all had BMI >35  At 2 years, diabetes remission occurred in 75% of their gastric bypass group, 95% of their biliopancreatic-diversion group and in no patients receiving intensive medical therapy patients. HgbA1C had similar rates of improvement as the 1st study: 6.3 in gastric-bypass, 4.9 in biliopancreatic-diversion group, and 7.7 in medical-therapy group.

While surgery has risks (see related material below), its benefits are likely to alter future treatment strategies with surgery being contemplated prior to exhausting all medical treatments.

Additional References:

  • -JAMA 2012; 307: 56-65.  Bariatric surgery and long-term cardiovascular events.
  • -JAMA 2011 [doi: 10.1001/jama.2011.817]). Large study failed to show that roux-en-Y gastric bypass prolonged life. n=850 VA pts to 41,244 controls. Same group showed no cost savings during initial 3 yrs: Med Care 2010; 48: 989-98.
  • -NEJM 2011; 365: 1365. Increased frequency of bariatric surgery in adolescents.
  • -NEJM 2009; 361: 445/520. perioperative safety.
  • -NEJM 2007; 357: 741, 753, 818. Bariatric surgery improves mortality rate.
  • NEJM 2007; 356: 2176. Review

Complications from surgery:

  • Early: bowel obstruction, DVT, GI bleed, leaks, pulmonary embolism, wound infection
  • After 30 days: anastomotic stricture, bowel obstruction, gallstones, dehiscence, fistula, Bleeding, Incisional hernia, nutrient deficiencies (iron, B12; calcium, Vit D (w RYGB), folate, B6/riboflavin).
  • Complications from gastric band: food impaction, erosion (now banned in Finland!), band slippage, gastric volvulus, band too tight, port infection
  • Roux-y gastric bypass:
    anastomotic leak 1.2%, anastomotic ulcers/stricture
  • Nutrient Monitoring–every 3months x 3, then yearly: Vitamin A, B12, Folate, Ceruloplasmin, Vit D-25OH, Iron studies, Zinc, thiamine, Selenium, Intact PTH, Mg, PT/PTT
  • Suggested supplements: Calcium c vitamin D 1200-2000mg, Iron at least 18-27mg/day, MVI with zinc/selenium
  • Also if duodenal switch, add Vitamin A 10,000 IU, and Vitamin D3 1200units daily or 50,000 units weeekly, Vitamin K 300 mcg,

Potential nutritional deficiencies:

  • B12, B6 (pyridoxine), Riboflavin (B2), B1 (Thiamine), Folate (B9)
  • Vitamins A,D,E, K
  • Calcium, Copper, Iron, Selenium, Zinc

Recommendations from NASPGHAN Post-Graduate Course 2011:

  • If post-op pain: epigastric –>do EGD & if neg do ‘RUQ w/u’, RUQ –> check U/S, LFTs possibly CT
  • If post-op vomiting –>do EGD
  • If post-op nausea –>Rx PPI and EGD if not improving
  • Anastomotic stricture in stomach –>dilate to 10-12mm in 1 session

Related blog posts (includes additional references)

Cardiovascular disease for the entire family

Staggering cost of obesity

A liver disease tsunami

Lower leptin with physical activity