S P E C I A L E D I T I O N 2012

Updates for physicians on practices, advances and research from Cleveland Clinic’s Endocrinology & Metabolism Institute

Endocrine Notes

{Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently}

Endocrine Notes | 1 | 2011

Dear Colleagues,Surgery Works for Diabetes.

The STAMPEDE story began more than 10 years ago. In 2003, Philip R.

Schauer, MD, published an intriguing study1 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 cardio-

vascular 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 endocri-

nologist 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 as-

signed 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 signifi-

cantly 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 outstand-

ing 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.

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 NotesChairman, 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.

© 2012 The Cleveland Clinic Foundation

1. Ann Surg. 2003 October; 238(4): 467–485. 2. N. Engl. J. Med. 2012 April 26 [V. 366, No. 17]

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A Diabetes Treatment That is Worthy of Note By P h I L I P S C h A u E r , m D

In March 2012, we were pleased

to present the findings of a ran-

domized controlled trial comparing

bariatric surgery and medical treat-

ment 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

27-43 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 man-

aged, 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 begin-

ning 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 cardio-

vascular 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 ac-

companied 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.”

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 com-

plications were dehydration, managed

with intravenous fluids. A single patient

developed a surgical-site gastrointestinal

leak which resolved with surgical treat-

ment. Four of the 100 surgical patients

required additional surgeries to address

these complications during the post-

surgical 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 gall-

bladder 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 diabe-

tes 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 sur-

gery compared with intensive medical

treatment for patients with obesity

and type 2 diabetes. Given the good

safety profile of bariatric surgery, clini-

cians should consider recommending

surgery for patients with uncontrolled

diabetes and obesity. ■

Our high-volume

bariatric surgery practice

at Cleveland Clinic has

better outcomes than

the national average.

Endocrine Notes | 2 | Special Edition 2012

An Endocrinologist’s View: Two-Year Follow-Up By S A N g E E TA k A S h y A P, m D

T he STAMPEDE trial showed

that two methods of bariatric

surgery resulted in marked

weight loss and biochemical remission

of diabetes as measured by blood glu-

cose 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 remis-

sion – 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 mecha-

nism 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’ du-

ration. 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 two-

year results were startling: The patients

who’d had gastric bypass had normal

glucose levels of 85-100 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 follow-

ing a physiological liquid mixed meal.

These effects were associated with

a remarkable 5.8 fold increase in over-

all pancreatic beta cell function.

Both bariatric surgery procedures stimu-

lated 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 re-

stores 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. ■

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.

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Good News from an Unexpected Quarter By S T E v E N N I S S E N , m D

T he obesity epidemic is emerg-

ing 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 ag-

gressive 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 authori-

ties 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 physician-

scientists 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 ad-

vantage of working in

a multispecialty group

practice culture that

promotes innovative

research.

STAMPEDE was

a comparison

of intensive medi-

cal therapy alone

versus medical

therapy plus bariatric

surgery. (Some have

characterized the

comparison as being

with bariatric surgery

alone. All patients re-

ceived very aggressive

medical treatment.)

The subjects were patients with uncon-

trolled type 2 diabetes. The paper was

published in the New England Journal

of Medicine in April 2012. As one of the

first controlled trials to test the effective-

ness 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 biochemi-

cal 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 effective-

ness 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 culminat-

ing 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 endocrinolo-

gists, bariatric surgeons and primary

care physicians to pursue the most

promising treatments for diabetes

and slow its devastating growth. ■

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