STAMPEDE: Bariatric Surgery Betters

Meds in Obese Diabetics

Lisa Nainggolan

March 31, 2014

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WASHINGTON, DC (updated) Three-year results from the STAMPEDE trial indicate

that bariatric surgery is better than intensive medical therapy alone when it comes to
achieving glycemic control in obese patients with uncontrolled type 2 diabetes.

The results "add to some fairly convincing evidence that, simply put, surgery is superior to
medical treatment for type 2 diabetes in terms of the classic end point of therapy that
doctors use around the world, and that is blood sugar control," said lead author of the study,
Philip Schauer, MD, from the Cleveland Clinic, Ohio, in an interview with Medscape
Medical News. Senior author Sangeeta Kashyap, MD, an endocrinologist, also from the
Cleveland Clinic, presented the findings today during a late-breaking clinical-trial session
at the American College of Cardiology 2014 Scientific Sessions.

The new findings, which were published simultaneously in the New England Journal of
Medicine, are also a "significant advance over our previous publication, in that we now are
able to show durability of the effects of surgery, with an intermediate duration of 3 years,"
said Dr. Schauer, a bariatric surgeon, who noted that this is the longest follow-up from a
randomized clinical trial comparing surgery with intensive medical therapy to date.

"There is no drug or combination of drugs that comes close to what surgery can do," he
stressed.
Dr. Schauer acknowledged, however, that there are many obese diabetes patients in whom
he would not consider bariatric surgery. "If a patient is well controlled, their HbA1c is 6.5%
on drugs and their [body mass index] BMI is 33, that's pretty good. I'm not saying every
patient with type 2 diabetes needs surgery, but it is underutilized, and we could be
improving the lives of [patients] and preventing disease if we did more bariatric surgery."

Asked to comment on the findings, endocrinologist Harold Lebovitz, MD, from the State
University of New York, Health Sciences Center at Brooklyn, who was not involved in the
study, told Medscape Medical News: "The 3-year follow-up data of the STAMPEDE trial
reinforces the difficulty in determining the role of metabolic surgery as a primary treatment
for type 2 diabetes.

"There can be little doubt that glycemic control and weight loss are superior in patients
undergoing metabolic surgery as compared with our current intensive medical therapy. On
the other hand, the surgical and nutritional complications as well as the occasional necessity
for reoperation are not to be dismissed as minor problems."

And little is known about the effects of metabolic surgery in reducing diabetic
complications, he added. "It will require extension of the STAMPEDE trial as well as
additional studies utilizing the STAMPEDE protocol and perhaps 10- or 15-year follow-up
data to determine the role of metabolic surgery in the primary treatment of type 2 diabetes."

Surgery Plus Medical Therapy vs Medication Alone

In STAMPEDE, 150 obese patients with uncontrolled type 2 diabetes average age 49
years, 66% female, mean HbA1c of 9.2% and average BMI 36.7 (range, 27 43) were
randomized to one of 2 bariatric procedures, gastric bypass surgery (n = 50) or sleeve
gastrectomy (n = 50), or to intensive medical therapy (n = 50).

At 3-year follow-up, an HbA1c level of 6.0% or less was achieved in 5% of medical-therapy

patients compared with 37.5% of gastric-bypass ( P < .001) and 24.5% of sleeve-
gastrectomy patients (P = .012), with less use of glucose-lowering medications including
insulin among the surgery patients.

Dr. Schauer stressed, therefore, that this was not really a trial of surgery vs medication. "It's
a misnomer saying it's surgery vs medical treatment, it's really surgery and medications vs
medical treatment."

Secondary end points, including BMI, body weight, triglycerides, HDL cholesterol, use of
cardiovascular and glucose-lowering medications, and quality of life also showed favorable
results 3 years after surgery compared with intensive medical therapy alone.

Of patients who had gastric bypass, 35% maintained normal blood sugar (HbA1c < 6%) on
no medications at 3 years, and 90% of surgery patients were able to be weaned off insulin
completely. "While some patients may achieve complete remission, others experience a
marked reduction in need for pharmacological treatment," Dr. Schauer said.
Dr. Lebovitz observed that the weight loss seen in the surgical patients was "remarkable." A
mean weight loss of 26.2 kg at 3 years followed gastric bypass, and the figure for sleeve
gastrectomy was 21.3 kg, compared with 4.3 kg for intensive medical therapy.

"The improvement in glycemic control correlated quite well with the magnitude of weight
loss," he added. And metabolic surgical procedures reduced the number of antihypertensive
and lipid-lowering agents required per day "but did not significantly lower mean blood
pressure or plasma LDL-cholesterol compared with the baseline values," he noted.

Cardiologist Amit Khera, MD, from the University of Texas Southwestern Medical Center,
Dallas, who was asked to comment on STAMPEDE during a press conference after the
presentation, said the results indicate that bariatric surgery "does seem to be quite durable.
Most of the benefit in terms of improving HbA1c in normalizing blood sugar seems to be
retained at 3 years," he observed.

Slow Creep of Blood Glucose, so Tight Follow-up Needed

Everyone stressed, however, that good follow-up is key for durability, for the surgery
patients to try to maintain weight loss and good glycemic control. Nevertheless, Dr.
Schauer acknowledged there is a slow creep up in blood sugar levels over time.

"If you look at our study results at 1 year, patients in the surgical group decreased HbA1c by
3 percentage points, which is amazing it went from about 9% to 6%. The medical group
dropped by about 1.75%, from about 9% to 7.5%."

After 3 years, "while there has been a slight increase in the average HbA1c in the surgical
group, very small, the patients in the medical group and these are folks who are
continuing to receive fairly intense medical treatment including over half on insulin
have deteriorated quite dramatically."

Diabetes "is a progressive disease everybody gets worse over time, so yes, while there
is, even after surgery, a slow creep of blood sugar, what happens with the medical group is
even worse," he stressed.

Dr. Kashyap explained that lifelong support is required. All patients during the trial were
counseled for lifestyle every 3 months in the first 3 years and then every 6 months during
the last year, and she stressed that this needs to continue indefinitely even in the surgery
patients.

"Surgery is a tool that initiates the weight loss, but lifestyle will never go away. In fact, it's
not uncommon, years out, to see weight regain [among surgery patients]. And so lifestyle
interventions are always the key, and these patients need ongoing support."
Balance Risk/Benefit, but Surgery Improved Quality of Life

Counseling of patients prior to surgery is also important to stress all of these issues, Dr.
Kashyap explained, adding that obese diabetic patients who are eligible for surgery tend to
be "very opinionated" about the procedure. "They either want it, or they absolutely want
nothing to do with it, and a lot of it is shaped by fear of having surgery." It is important that
patients understand "this is a major operation; there could be complications," she noted.

And many endocrinologists are uncertain about bariatric surgery too, she added. "But for
those who are difficult to manage, and we know that they are obese, surgery is a therapeutic
avenue for patients it's something that physicians need to consider. Continuing
medications without much benefit does not make sense. The treatment is weight loss."

Patients and their doctors need to remember that "diabetes is a silent killer," she added.
"Often people have the heart attack or dialysis and then [want to] consider [bariatric
surgery], but it's really far too late by that point."

Dr. Schauer said it will always remain important to balance the risks of the intervention
with the benefits. "While we did have expected complications of surgery in the first year
we had 4 reoperations out of 100 patients, so a 4% reoperative rate there were no deaths
and there were no complications that resulted in long-term major disability."

Dr. Lebovitz said: "The better improvement in glycemic control by gastric bypass and
sleeve gastrectomy was counterbalanced by a significant incidence of surgical
complications such as gastrointestinal strictures, ulcers, and leaks, as well as intra-
abdominal bleeding and dumping syndrome (13 complications in gastric bypass and 5 in
sleeve gastrectomy as compared with 2 in patients with intensive medical therapy).

And nutritional and metabolic complications "were also greater in the surgically treated
patients," he added.

But for the first time, the STAMPEDE investigators employed the SF-36 questionnaire and
found that the surgical group was happier than the medical group; there was a "marked
improvement in quality of life," Dr. Kashyap said. This "comes from not taking so many
agents insulin is incredibly burdensome," she noted.

Dr. Schauer agreed: "The quality of life is substantially better The patients are not taking
as much insulin, they are not checking their blood sugar 3 or 4 times a day, and they are on
fewer medications. Not only that, but their blood sugar is even better."
A significant number of these patients also have comorbid conditions such as osteoarthritis,
and "they gained greater mobility," Dr. Kashyap added. And in general, likely due to the
weight loss, the surgical group had "greater confidence in a social setting," she observed.

Dr. Khera said that, to his mind, the quality-of-life data were key. "We know that when
patients have bariatric surgery there are some dietary changes, there can be some
complications, but all told, when you look at that balanced against change in medications
and weight loss, there was a significant improvement in quality of life, and that is a really
important component."

Bariatric Surgery Way Underused in the United States, but Question Mark over BMI
3035

The STAMPEDE results are also some of the first to address use of bariatric surgery in a
randomized fashion in patients with a BMI less than 35, said Dr. Schauer, noting that most
clinical guidelines and insurance coverage for bariatric surgery limit access to patients with
a BMI of 35 kg/m2 or greater. "A little more than a third of our patients had a BMI of less
than 35." he said, and "when you look those people they enjoy the same type of benefits as
those BMI greater than 35. We clearly showed that."

Indeed, bariatric surgery currently "is way underutilized in the US," Dr. Schauer added.
"There are about 200,000 surgeries per year: compare that with coronary artery bypass graft
[CABG] surgery at its peak, which was 700,000 or 800,000 cases per year, and that's an
operation that was 3 times the cost of bariatric surgery."

Indeed recent National Health and Nutrition Examination Survey (NHANES) data "suggest
that less than 50% of patients in America who have a diagnosis of type 2 diabetes are
actually at the appropriate threshold, HbA1c of 7%," he added.

"That tells us that even with current drug therapy, half are not in good control, and only
18% were in good control with blood sugar, BP, and cholesterol. So medical treatment
definitely has its shortcomings, and the real news here is that surgery offers an opportunity
for people who are not well controlled with medical treatment to get in control."

But Dr. Khera said in the press conference that there is still a question mark over the
patients with BMI of 30 to 35, "which is not currently a group where bariatric surgery is
indicated." Given that the mean BMI overall in the study was between 36 and 37, "I think
we need some more specific data in the 30-35 group; that would be valuable information,"
he commented.

Bypass Best Despite Trend for Sleeve Gastrectomy

Speaking finally to the issue of the benefits of gastric bypass vs the other surgical
procedure employed, sleeve gastrectomy, both of which are performed laparoscopically, Dr.
Schauer said, "This study was mainly designed to look at surgical vs medical therapy. We
were able to see some differences between the 2 procedures, but it wasn't really powered
enough to really demarcate the differences in that way."

Nevertheless, "We did see greater weight loss with gastric bypass and a higher percentage
of patients with bypass achieved good glycemic control, like HbA1c 7% or less, and they
had a greater reduction in medication use and so forth."

However, he acknowledged, "There is an international trend of increasing popularity of

sleeve gastrectomy.

"But I still think for people with diabetes, particularly more advanced diabetes, based on
what we know now in this trial, that gastric bypass is the better option in terms of efficacy,"
he said.

Dr. Kashyap told Medscape Medical News: "The sleeve did very well in our study. For both
procedures, the A1c reduction was quite tremendous. The only thing we saw with the sleeve
was that there was greater relapse, and we think it's because people who have the sleeve
don't lose as much weight as those who have gastric bypass, and in our study weight loss
was the primary driver for improvement in glycemic control."

Dr. Schauer has received research grants from Ethicon Endo-Surgery and the National
Institutes of Health; educational grants from Stryker Endoscopy; honoraria from Ethicon
Endo-Surgery as scientific advisory board member, consultant, and speaker and from Lilly,
Novo Nordisk, and Nestle as a speaker. He has been a consultant/advisory board member
for RemedyMD, Barosense, and Surgiquest. Conflicts for coauthors are listed in the article.
Dr. Lebovitz is on the advisory board of several companies developing investigational
drugs or devices for diabetes, including Biocon, Intracia, Metacure, and Poxel Pharma,
and he consults for AstraZeneca, Janssen, and Sanofi on scientific issues