IBSR Newsletter - Summer 2005

Summer 2005

IBSR Newsletter

Summer 2005 Volume 20, number 2

Obesity Surgery, Insulin, GLP-1 and Cancer –A Literature Review

by Edward E. Mason MD, Ph.D.

In a study of 900,000 adults followed for 16 years, Calle, et al, found the death rate from cancer was increased by 52 percent in men and 62 percent in women when the initial BMI was 40 or more. Cancers of the esophagus, colon and rectum, liver, gall bladder, pancreas, kidney, non-Hodgkins lymphoma and multiple myeloma were increased in both men and women. Stomach and prostate cancer was increased in men. Breast, uterus, cervix and ovary cancer were increased in women. They estimated, on the basis of this study, that overweight and obesity could account for 14 percent of all cancer deaths in the United States in men and 20 percent in women.¹ Coughlin, Calle, et al, found that diabetes was an independent predictor of mortality from cancer of the colon, pancreas, female breast; and, in men, of the liver and bladder cancer.² Christou, et al, found that patients who had Roux-en-Y gastric bypass seemed to derive protection from death caused by cancer while the obese who were not treated surgically had a higher frequency of death from cancer.³ Diabetes was found to be a predictor of death in a study of 18,972 patients from the International Bariatric Surgery Registry (IBSR).⁴ Preliminary examination showed that cause of death from cancer was less common for bypass operations than pure restriction operations (unpublished data). This could be due to the greater reduction in weight with bypass but it may also be due to the lower insulin levels due to the stimulation of GLP-1 secretion.

Insulin stimulates growth of cancer cells. Serum insulin levels increase with increasing body weight. Lowering elevated serum insulin in overweight and obese patients, without a diagnosis of diabetes, prevents cancer and decreases cancer deaths. The decrease in cancer frequency and lethality would appear to result from the decrease in serum insulin levels that occur when the incretin deficiency of obesity is corrected. The result is a decrease in cancer deaths in the competing causes of mortality. It appears that GLP-1 not only prevents and cures type II diabetes mellitus (T2DM) but also decreases the risk of cancer that occurs because of overweight and obesity. High insulin levels increase cancer risk even in patients who are not diabetic.

After bypass operations for obesity the serum levels of GLP-1 rise from subnormal levels to a normal response to a meal.^5,6,7 They continue to rise to higher than normal levels over the years. Misbin, O’Leary and Pulkkinen reported decreased insulin receptor binding and elevated serum insulin levels in 1979.⁸ O’Leary and Duerson reported the decrease in serum insulin levels after intestinal bypass the following year.⁹ Bypass operations for obesity that expose the distal ileum to undigested food, result in an increased secretion of GLP-1. Improved insulin receptor activity, as a result of increased GLP-1 secretion, results in a decrease in serum insulin. Gastric bypass allows hypertonic stomach contents to enter the small bowel by bypassing the pyloric muscle. Normally intestinal contents are maintained isotonic with body fluids but, when the duodenal osmoreceptors no longer control passage of gastric contents into the duodenum, the hypertonic contents stimulate peristalsis, rapid transit, and secretion of the ileal-brake hormone, GLP-1. This is the most logical explanation of the rise in GLP-1 in response to meals that is observed after gastric bypass.^10,11

T2DM does not respond to insulin because it is due to a deficiency of incretins, hormones secreted by the gut that are both exocrine and endocrine. Surgeons have the ability to provide both GLP-1 and a built in servomechanism that stimulates GLP-1 when glucose and fat are ingested. We do not know the lifelong effects in sufficient numbers of patients. Preventing diabetes and cancer through bypass operations should prolong life. However, bypassing the upper gastrointestinal tract or most of the small bowel may, over many years, introduce new risks that could have been avoided by a simple restriction operation. Sjöström recommended that we use simple restriction for patients with morbid obesity and only consider bypass operations for the super obese.¹² It is possible that a “once a day” injection of an analog of GLP-1, along with a restriction operation, could substitute for bypass. There are at least two companies that have a GLP-1 type medication close to market. These will require a daily injection because of the size of the molecule. There may be small molecule medications that can be taken by mouth at some time in the future. One advantage of a medication is that it can be stopped, or the dosage adjusted.

Bypass operations cause increasing endogenous dosage for at least 20 years.⁵ GLP-1 and the derivatives do not directly cause hypoglycemia because they are only active when serum glucose is above normal. However, it is possible that some patients over their remaining life may develop nesidioblastosis from prolonged and increasing GLP-1 stimulation of beta cell growth. To diagnose iatrogenic nesidioblastosis will require study of patients who develop symptoms of hypoglycemia years after bypass operations.

With millions of patients undergoing bypass operations, and with the extensive and growing literature about GLP-1 and related medications, the late-in-life effects need much more study. Bariatric surgery makes geriatric care possible for these patients but should not make it necessary, especially if simple and more physiologic anatomy and function, plus use of medication, could avoid adverse lifelong effects of a bypass operation. It is important that the comparison of bypass and simple operations upon longevity be continued. The IBSR needs continued participation of obesity surgeons to continue study of life long effects following surgical treatment for severe obesity.

1. Calle EE, Rodriguez C, Walker-Thurmond K, Thun JJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. NEJM 348:1625-38, 2003.

2. Coughlin SS, Calle EE, Teras LR, Pertrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. American Journal of Epidemiology 59: 1160-7, 2004.

3. Christou NV, Sampalis JS, Liberman M, Look D, Auger S, McLean AP, MacLean LD. Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Annals of Surgery 240: 416-23, 2004.

4. Zhang W, Mason EE, Renquist KE, Zimmerman MB, IBSR Contributors. Factors influencing survival following surgical treatment of obesity. Obesity Surgery 15:43-50, 2005.

5. Naslund E, Blackman L, Holst JJ, et al. Importance of small bowel peptides for improved glucose metabolism 20 years after jejunoileal bypass of obesity. Obesity Surgery 8:253-260, 1998.

6. Kellum JM, Keummerle JF, O’Dorisio TM, et al. Gastrointestinal hormone response to meals before and after gastric bypass and vertical banded gatroplasty. Annals of Surgery 211:763-771, 1990.

7. Valverde I, Puente J, Martin-Duce A, et al. Changes in glucagons-like peptide-1 (GLP-1) secretion after biliopancreatic diversion or vertical banded gastroplasty in obese subjects. Obesity Surgery 15: 387-397, 2005.

8. Misbin RI, O’Leary JP, Pulkkinen. Insulin receptor binding in obesity. A reassessment. Science 205: 1003-1004, 1979.

9. O’Leary JP, Duerson MC. Changes in glucose metabolism after jejunoileal bypass. Surg Forum 31: 87-88, 1980.

10. Mason EE. Ileal transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery. Obes Surg 9:223-228, 1999.

11. Mason EE. The mechanisms of surgical treatment of type 2 diabetes. Editorial. Obes Surg 15:459-461, 2005.

12. Sjöström L. Surgical intervention as a strategy for treatment of obesity. Endocrine 13: 213-230, 2000.

A History of the First Registry for Surgical Treatment for Severe Obesity

By Kathleen Renquist, BS

The American Society for Bariatric Surgery was born in 1983 at the University of Iowa. Under the direction of Dr. Edward E. Mason, the need for standardized data collection and analyses led to the development of the first registry specifically designed to study outcome for surgical treatment for severe obesity. This was before the term “outcome” became popular or the “New Era of assessment and accountability in medical care” was ushered in by Arnold Relman MD.^1,2

The first report of the National Bariatric Surgery Registry (NBSR) in 1980 contained data from jejunoileal bypass takedowns, loop gastric bypass, Roux-en-Y bypass, and gastroplasty.³ Women outnumbered men by 8 to 1. Preoperative hospital stay averaged three days and postoperative hospital stay varied according to type of operation from 8 to 11 days. Thirty-day operative mortality was 1.1%, with respiratory failure the major cause of death. Complications presenting with a frequency greater than 1% were gastrointestinal leaks, pulmonary emboli, wound infection and subphrenic abscess. Compared to today, operative mortality was higher and hospital stay was longer.

In 1986, the NBSR produced the first standardized personal computer software for obesity surgery outcome. All 110 ASBS surgeons were provided NBSR membership free for 1986 and 1987 with a nominal charge ($150.00) assessed for software. A survey of NBSR members in 1987 revealed 10% had incompatible computer systems, another 10% had no computer at all, 18% were sending data, 53% were either beginning to use the software or using it, and 9% withdrew.

The ASBS has seen an unprecedented rise in surgeon membership since 1996, largely due to an increase in popularity of bariatric surgery. With the increase in bariatric surgery, pressure to provide accountability in outcomes has also increased. Competition in the market place for net-workable and web based systems has cut into the IBSR membership. However, life long comparisons using significant operation numbers is a continuing need in surgical treatment of obesity. Using the National Death Index (NDI), the IBSR published a survival analysis comparing operation categories.⁴ An NIH grant for another NDI search to 2003 has been submitted which will compare information from 35,866 IBSR patients and provide a more comprehensive long-term comparison of operative type and cause of death.

The historical IBSR database now has 43,500 patient records contributed by 85 data collection sites representing the surgical experience of 117 surgeons. IBSR Reports have provided risk-adjusted comparisons of 30-day complications and quality of life analyses. Changes in weight, hypertension, and diabetes have been reported when sufficient follow-up was available. NBSR/IBSR publications include 77 newsletter issues, 12 articles in refereed journals, nine published abstracts, 34 aggregate statistical reports, more than 400 individual surgeon reports, eight special studies, and seven instruction manuals to accompany the 13 personal computer software versions.

All patients need to know what operation extends life. The IBSR and the Swedish Obesity Subjects (SOS) have the possibility of >10 year follow-up for mortality, but SOS has fewer bypass patients.⁵ What sets the IBSR apart from other bariatric surgery software vendors or registries is the opportunity to compare lifelong survival for U.S. patients by operative type.

1. Tarlov AR, Ware JE, Greenfield S, Nelson ED, et al. The medical outcomes study: An application of methods for monitoring the results of medical care. JAMA 262 (7): 925-930, 1989.

2. Relman AS. Assessment and accountability: The third revolution in medical care. NEJM: 319(18), 1220-122, 1988.

3. Scott DH. Registry. Bariatric Surgery Workshop, May 29 &30, Iowa City Iowa, page 122-124, 1980.

4. Zhang W, Mason EE, Renquist K, Zimmerman B, IBSR Data Contributors. Factors Influencing Survival Following Surgical Treatment of Obesity. Obesity Surgery 15: 43-50, 2005.

5. Sjöström L, Lindroos A, Peltonen M, Torgerson J, et al. Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric Surgery. NEJM 351: 2683-2693, 2004

A Tribute of John D, Halverson MD

By Kathleen Renquist

_{Dr. John Halverson was one of the most energetic persons that I have ever
known. He was a staunch proponent of both
surgical treatment for severe obesity and the importance of outcome analyses. He was a charter member of the NBSR. My first meeting with him was at the 1987 ASBS
meeting in St. Louis,
which he hosted. When he moved to Syracuse NY from St. Louis MO
in 1999, his former data collection system became out of date for Y2K. He then rejoined the IBSR, and began
collecting data using IBSR software.
Thanks to his dedication, and that of his staff, their first data
contribution was only a few months later.
In 2003, the IBSR provided a graphic of %EWL for RGB and VBG/SRG
patients as a special study for a presentation he was to give for the ACS (fig.
1). Based on his interest, we were working
together on a logistic regression analysis of %EWL in the fall of 2004 and
hoped to submit an abstract for the 2005 ASBS meeting. Unfortunately, he “did not have time” to
complete the abstract and paper. This valued surgeon, and friend of the IBSR, died at his
home January, 2005. His support,
expertise and enthusiasm are greatly missed.}

Figure 1. IBSR %EWL as presented by Dr. Halverson to the ACS in 2003. Data Source: IBSR Merge 16(2): N=7,782. Follow-up rates RYGB = 40.6%, VBG/SRVG = 37.5%.

SUMMER 2005 IBSR Newsletter Volume 20, Number 2