Endocrine Notes. {Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently} SPECIAL EDITION

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1 Endocrine Notes Updates for physicians on practices, advances and research from Cleveland Clinic s Endocrinology & Metabolism Institute {Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently} SPECIAL EDITION 2012

2 Dear Colleagues, Surgery Works for Diabetes. The STAMPEDE story began more than 10 years ago. In 2003, Philip R. Schauer, MD, published an intriguing study 1 documenting the effects of gastric bypass surgery on biochemical control of diabetes. Dr. Schauer looked at diabetic patients who d had the Roux-en-Y gastric bypass surgery and noted a significant improvement in diabetes mellitus as measured by patients reduced need for medications designed to bring blood sugar under control. While this finding was hopeful, the response from endocrinology and cardiovascular specialists was muted. What was needed was a demonstration that bariatric surgery could unequivocally produce biochemical resolution of the disease. In 2007, Dr. Schauer, now Director of Cleveland Clinic s Bariatric & Metabolic Institute within the Endocrinology & Metabolism Institute, along with colleagues Steven Nissen, MD, Chair of Cardiovascular Medicine, and endocrinologist Sangeeta Kashyap, MD, launched STAMPEDE (Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently) to prove the safety and efficacy of surgical treatment for diabetes. The results were published in the New England Journal of Medicine. 2 STAMPEDE enrolled patients with uncontrolled type 2 diabetes and randomly assigned them to medical therapy, Roux-en-Y gastric bypass or sleeve gastrectomy. The endpoint was a level of glycated hemoglobin lower than 6 percent at one year. The result? All three groups improved. But the surgical group enjoyed significantly greater improvement than the others, with lower-to-no need for insulin or cardiovascular medications. STAMPEDE is a landmark clinical trial, extremely well-controlled with outstanding medical treatment in both the surgical and pharmaceutical arms provided by our expert endocrinologists under the direction of Dr. Kashyap. The findings are meaningful and applicable to the population at large. The STAMPEDE team is currently seeking funding to attempt to replicate these results in a larger, multicenter trial. If it is able to do so, endocrinologists will have a powerful new tool in their diabetes mellitus treatment armamentarium. 1. Ann Surg October; 238(4): N. Engl. J. Med April 26 [V. 366, No. 17] Sincerely, James B. Young, MD Chairman, Endocrinology & Metabolism Institute Professor of Medicine and Executive Dean, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University George and Linda Kaufman Chair Physician Director, Institutional Relations and Development Endocrine Notes Chairman, Endocrinology & Metabolism Institute James B. Young, MD Managing Editor Kimberley Sirk Art Director Mike Viars Marketing Bill Sattin, PhD Mary Anne Connor Endocrine Notes updates physicians on clinical practices, advances and research from Cleveland Clinic s Endocrinology & Metabolism Institute. It is written for physicians and should be relied upon for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient The Cleveland Clinic Foundation Endocrine Notes

3 A Diabetes Treatment That is Worthy of Note By Philip Schauer, md In March 2012, we were pleased to present the findings of a randomized controlled trial comparing bariatric surgery and medical treatment for the management of type 2 diabetes at the annual meeting of the American College of Cardiology and published in the New England Journal of Medicine. The single-center study randomized 150 obese patients (BMI kg/m2) with poorly controlled diabetes (mean A1c > 9 percent) to receive either sleeve gastrectomy, Roux-en-Y gastric bypass or intensive medical therapy - secondary endpoints related to cardiovascular risk. All three groups showed improvement in blood sugar level at the end of one year. Of the patients who were medically managed, 12 percent achieved the primary endpoint of hemoglobin A1c of 6 percent, compared to 37 percent of those receiving sleeve gastrectomy and 42 percent having gastric bypass. (The average BMI for patients at the beginning of the study was 36. The patients randomized to surgery lost about 60 pounds, with a post-treatment BMI of about 26.) Patients in the surgery group also had greater reduction in cardiovascular risk factors and reduced their dependency on diabetes and cardiovascular medications. These findings are worthy of note by all who are concerned by the prospect of managing what all signs indicate will be an increasing number of new diabetes cases in coming years. Indeed, an editorial that accompanied the study s publication in the New England Journal of Medicine described the diabetes curve as one of the fastest growing epidemics in human history. Our high-volume bariatric surgery practice at Cleveland Clinic has better outcomes than the national average. Until now, diabetes has been seen as a medical problem amenable only to medical treatments. This study demonstrates that surgery is superior to medical treatment in achieving glycemic control for patients with uncontrolled diabetes. Proposing a surgical solution inevitably brings up the question of risk. In our study, the most common complications were dehydration, managed with intravenous fluids. A single patient developed a surgical-site gastrointestinal leak which resolved with surgical treatment. Four of the 100 surgical patients required additional surgeries to address these complications during the postsurgical year. There were no deaths, long-term disability or life-threatening complications. Our high-volume bariatric surgery practice at Cleveland Clinic has better outcomes than the national average. Nationally, 15 to 20 percent of patients undergoing these procedures have mild complications, 1 percent has serious complications and 2 in 1,000 dies (similar to the mortality figures for gallbladder surgery). There is no question that patients seeking bariatric surgery should seek out surgeons and centers like Cleveland Clinic that have a great deal of experience. We also hear commentary on the implied economics of the study. The surgeries we studied involved costs of around $25,000. Theoretically, most patients with diabetes mellitus can control their blood sugar with diet, exercise and medication. However, many patients with uncontrolled diabetes on medical therapy will experience complications including heart and kidney disease, or loss of limbs and vision and millions of dollars may be expended to treat conditions that we now believe could be prevented by timely surgical intervention. The STAMPEDE study is one of the first randomized controlled trials demonstrating the superiority of surgery compared with intensive medical treatment for patients with obesity and type 2 diabetes. Given the good safety profile of bariatric surgery, clinicians should consider recommending surgery for patients with uncontrolled diabetes and obesity , ext clevelandclinic.org/endonotes

4 An Endocrinologist s View: Two-Year Follow-Up By sangeeta kashyap, md The STAMPEDE trial showed that two methods of bariatric surgery resulted in marked weight loss and biochemical remission of diabetes as measured by blood glucose levels. However, among patients who received either the Roux-en-Y gastric bypass or sleeve gastrectomy, those having the bypass achieved significantly higher rates of remission 33 percent as opposed to 10 percent at the two-year follow-up. Yet both groups had a similar reduction in body weight and BMI, suggesting that weight loss was not the only mechanism for remission. A metabolic substudy of the two-year extension of STAMPEDE gave us the answer. We learned that the gastric bypass resulted in a significantly larger loss of abdominal fat compared with the sleeve gastrectomy about 5 percent more. We looked at meal glucose responses in the first 60 patients who had been randomized to one or the other of the surgical groups. They were mostly in their late 40s with a mean BMI of 36 and diabetes of seven to 10 years duration. Many had metabolic syndrome. All were on medication, some on three or more, and half required insulin. Both groups were at a baseline of 150 mg/ dl at the beginning and 250 mg/dl at the end of meal intake. But the twoyear results were startling: The patients who d had gastric bypass had normal glucose levels of mg/dl before and after meal intake. The sleeve gastrectomy group had intermediate glucose levels despite having lost the same amount of weight. At both 1 and 2 years follow-up, the gastric bypass patients had achieved nearly normal glucose tolerance following a physiological liquid mixed meal. These effects were associated with a remarkable 5.8 fold increase in overall pancreatic beta cell function. A substudy of two-year results of STAMPEDE gave us the answer. We learned that the gastric bypass resulted in a significantly larger loss of abdominal fat compared with the sleeve gastrectomy about 5 percent more. Both bariatric surgery procedures stimulated insulin production and incretins with markedly increased postprandial GLP-1 levels, as noted in previous observational studies of obese patients with type 2 diabetes. Greater effects on insulin sensitivity were noted with gastric bypass compared with sleeve gastrectomy, despite similar weight loss.both procedures produced similar weight loss, reduction in body fat and leptin levels. However, greater reduction in abdominal fat was noted with gastric bypass than sleeve gastrectomy. So we conclude that in moderately obese patients with uncontrolled type 2 diabetes, bariatric surgery provides more durable glycemic control compared with intensive medical therapy at two years. Despite similar weight loss as sleeve gastrectomy, gastric bypass uniquely restores pancreatic beta cell function and reduces abdominal fat, targeting the key cardiometabolic defects in diabetes. Medical therapy has always targeted pancreatic hormonal failure to slow down the advancement of the disease. Our findings suggest that bariatric surgery could potentially reverse the disease and maybe stop it in its tracks. It deserves the attention of endocrinologists and the entire medical community. Endocrine Notes 2 Special Edition 2012

5 Good News from an Unexpected Quarter By steven nissen, md The obesity epidemic is emerging as the greatest threat to 50 years of progress in reducing the burden of cardiovascular disease in developed countries. The incidence of type 2 diabetes has skyrocketed in recent years. Some projections suggest that by the year 2050, half of the U.S. population will develop diabetes during their lifetime. In our coronary care unit, about half of all patients are diabetic. Weight loss is highly effective at preventing the development of diabetes and also reduces obesity-related complications such as hypertension. But changing lifestyles and attitudes hasn t been easy. To overcome these limitations, we have to look outside the usual paradigms. The STAMPEDE trial provided an aggressive and highly effective approach to obesity and diabetes: bariatric surgery. Clinicians observed that obese diabetics who underwent bariatric surgery showed lower blood sugar levels within hours and days of the operation. Some authorities have suggested that the procedure altered gastrointestinal hormones, thereby helping to control diabetes. Some of these early observations originated from bariatric surgeons and endocrinologists at Cleveland Clinic, particularly Drs. Philip Schauer and Sangeeta Kashyap. These physicianscientists sought to investigate this phenomenon in depth. As Chair of Cardiovascular Medicine, I was proud to be asked to participate in the study that became known as STAMPEDE. The authors and their teams designed a randomized clinical trial that would provide strong and highly reliable data. We had outstanding support from the Cleveland Clinic Coordinating Center for Clinical Research in the design and execution of the trial, and the added advantage of working in a multispecialty group practice culture that promotes innovative research. STAMPEDE was a comparison of intensive medical therapy alone versus medical therapy plus bariatric surgery. (Some have characterized the comparison as being with bariatric surgery alone. All patients received very aggressive medical treatment.) The subjects were patients with uncontrolled type 2 diabetes. The paper was published in the New England Journal of Medicine in April As one of the first controlled trials to test the effectiveness of bariatric surgery in diabetics, the results received tremendous public and scientific attention. The medically treated patients did well. Twelve percent of the patients who received medicine alone saw their blood sugar drop to normal levels. But among the patients who got both medicine and surgery, the results were extraordinary. Almost half of this group saw their blood sugar return to normal. From a biochemical point of view, they were cured. We are gratified by what we ve learned from STAMPEDE, but we are not blind to the limitations of this study. It was a small, single-center study with only a year s follow-up. The bariatric surgery itself produced some modest adverse effects that need to be examined further. The study team is currently in the midst of a four-year extension study to look at long-term effects. We look forward to the larger, multicenter trials necessary to determine the effectiveness of bariatric surgery plus medicine on cardiovascular outcomes. Today, only about 1 percent of Americans who qualify for bariatric surgery are offered this treatment. Additional research confirming and extending our findings could increase the demand for bariatric surgery. Bariatric surgery can cost $25,000. When you compare the bill for a one-time bariatric surgery to the expenses incurred over a lifetime of diabetic care, often culminating in lengthy treatment for coronary heart disease, the surgery may be a good investment. STAMPEDE includes a five-year follow-up to assess the economic impact of the treatment. My colleagues and I look forward to continuing to work with endocrinologists, bariatric surgeons and primary care physicians to pursue the most promising treatments for diabetes and slow its devastating growth , ext clevelandclinic.org/endonotes

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