1. Results of the STAMPEDE Trial
Bariatric Surgery vs. Intensive Medical Therapy in Obese Diabetic Patients: 3-Year Outcomes
Results of the STAMPEDE Trial
Philip R Schauer, Deepak L Bhatt, John P Kirwan, Kathy Wolski,
Stacy A Brethauer, Sankar D Navaneethan, Ali Aminian,
Claire E Pothier, Ester SH Kim, Steve E Nissen, and Sangeeta R Kashyap
STAMPEDE investigators
It is my pleasure to present the 3 year follow up results of the STAMPEDE Trial. This study compares the effect of bariatric surgery vs. intensive medical therapy for the treatment of T2DM and obesity.
Cleveland Clinic
Bariatric and Metabolic Institute
Endocrinology, Diabetes and Metabolism

2. Disclosures
Research support: Ethicon Endo-Surgery, NIH, American Diabetes Association
Consulting and honoraria: Ethicon Endo-Surgery
STAMPEDE was funded by Ethicon Endo-Surgery, LifeScan Inc, Cleveland Clinic, and NIH-NIDDK
Research support and consulting relationships of the investigators are listed here and are available in the manuscript. This investigator initiated study was funded mostly by Ethicon Endosurgery and additional support came from LifeScan and NIH. Data collection and management was conducted by the Cleveland Clinic Cardiovascular Coordinating Center.

3. Background
T2DM affects over 25 million individuals in the US, but < 50% of patients achieve adequate glycemic control on current pharmacotherapy.
Observational studies show improvement in glycemic control and CV risk factors following bariatric surgery.
Short-term (1-2 yrs.) RCTs, including the 1 year data of the STAMPEDE trial demonstrated remission of T2DM following bariatric surgery*.
However, no long-term (>3 yrs) RCT data exist to compare the durability of bariatric surgery vs medical therapy for T2DM control.
*Schauer P, Kashyap S, Wolski K. et al, NEJM (17):

4. Objectives
Compare the durability of bariatric surgery vs medical therapy with respect to:
Achieving biochemical resolution of T2DM
2) Compare differences between types of surgery
The objective of this trial was to compare the success rate of an IMT regimen vs. bariatirc surgery to achieve biochemical remission of T2DM in pts with T2DM and moderate to severe obesity. The 2 surgical procedures included gastric bypass and sleeve gastrectomy.

5. Endpoints Primary Success rate of achieving HbA1c ≤ 6% Secondary
Change in fasting plasma glucose (FPG)
Change in lipids, blood pressure, BMI
Change in carotid intimal medial thickness
Change in medications
Safety and adverse events
Quality of Life
The primary end point was the success rate of achieving HBA1c ≤ 6%. Secondary end points included change from baseline in FPG, change in BMI (or weight loss), change in lipids, and blood pressure.. We also evaluated the effect of surgery on medication usage (diabetic and CV meds) as well as rate of adverse events.

6. Intensive Medical Therapy
Weight management with diet and lifestyle counseling per ADA clinical care guidelines*
Insulin sensitizers, GLP-1 agonists, sulfonylureas and multiple insulin injections utilized to target HbA1c ≤6%
Scheduled visits with nutrition, psychology and endocrinology per protocol
Follow-up visits every 3 months through year 2, and every 6 months for remaining follow up
Intensive medical therapy in this study encompassed ADA guidelines for standard therapy but went one step further with the intent to drive HbA1c to 6% or less. This was accomplished by incorporating diet and life style counseling, and the use of potent diabetes medications such as insulin sensitizers, GLP-1 agonists, sulfonylureas, and insulin. All patients were evaluated and counseled by dieticians and psychologist in preparation for possible bariatric surgery. All patients were instructed in frequent home glucose monitoring and self-titration of medications.
*Standards of medical care in diabetes Diabetes Care;34 Suppl 1:S11-61

7. Bariatric Surgery Roux-en-Y Gastric Bypass Sleeve Gastrectomy
Shown here are the 2 bariatric operations which are 2 of the most common bariatric procedures performed world-wide: Roux-en-Y Gastric Bypass (Gastric Bypass), and Sleeve Gastrectomy. Sleeve gastrectomy involves vertically stapling and excising the stomach to achieve approximately 75-80% stomach volume reduction leaving a narrow tubular stomach. Gastric Bypass involves stapling to create a small stomach pouch (15 mls) resulting in approximately 95% volume reduction. In addition, the jejunum is divided and connected to the gastric pouch while the proximal end of jejunum is reconnected creating a bypass of most of the stomach, duodenum and small portion of jejunum. These procedures are performed laparoscopically requiring very small abdominal incisions resulting in a hospital stay of about 2 days and recovery time of 2-4 weeks.
Roux-en-Y Gastric Bypass Sleeve Gastrectomy
Kashyap S, Schauer P, Bhatt D; Diabetes Obesity Metabolism2010 Sep;12(9):833

8. STAMPEDE Trial: Flow of Patients
218 patients screened
HbA1c >7.0%
BMI kg/m2
Age years
150 randomized 50
Intensive medical therapy alone 50
Medical therapy
plus
gastric bypass 50
Medical therapy
plus
sleeve gastrectomy
8 withdrew consent
2 Lost to follow-up
2 Lost to follow-up
1 withdrew consent
prior to surgery
This is the recruitment and retention diagram. 218 patients initially met inclusion criteria and desired to participate but 68 were ultimately excluded to reach the target enrollment of 150. The inclusion criteria included patients with HbA1c > 7%, BMI 27-43, and age Patients were randomized in a 1:1:1 ratio to the three treatment arms. 7 in the medical therapy group dropped out immediately after randomization, and 2 patients missed the 9m and 12 m visits. 1 patient in the sleeve gastrectomy group withdrew prior to surgery. The population for analysis was 41 IMT, 50 Gastric Bypass, and 49 Sleeve Gastrectomy. The overall retention was 93%.
Population for 3-Year Analysis
91%
retention

9. Baseline Characteristics
Parameter
Medical Therapy (n=40)
Bypass (n=48)
Sleeve (n=49)
Age (yrs)
50.3
48.0
47.8
Females
67%
58%
78%
Duration of diabetes (yrs)
8.8
8.0
8.3
HbA1c (%)
9.0
9.3
9.5
Body Mass Index (kg/m2)
36.4
37.1
36.1
≥ 3 diabetes medications
61%
52%
46.9%
Insulin use
51.2%
46%
44.9%
Depression
32%
37%
Microvascular complications
20%
42%
29%
Note: Based on analyzed population

10. Primary and Secondary Endpoints at 36 Months
Parameter
Medical Therapy (n=40)
Bypass (n=48)
Sleeve (n=49)
P Value1
P Value2
HbA1c ≤ 6% 5%
37.5%
24.5%
<0.001
0.012
(without DM meds) 0%
35.4%
20.4%
0.002
HbA1c ≤ 7%
40%
64.6%
65.3%
0.02
Change in FPG (mg/dL) -6
-85.5
-46
0.001
0.006
Relapse of glycemic control
80%
23.8%
50%
0.03
0.34
% change in HDL
+4.6
+34.7
+35.0
% change in TG
-21.5
-45.9
-31.5
0.01
% change in CIMT
0.048
0.013
0.017
0.36
0.49
Shown here are the key endpoints that were determined to be significantly superior in the surgical groups compared to medical therapy. The primary end point, HbA1c ≤6%, was achieved in 5% of IMT patients, 37% of Gastric Bypass patients and 24% of Sleeve Gastrectomy patients. Nearly all Gastric Bypass patients who achieve the primary end-point target, did so with out requiring any diabetic medications (oral or injectable) while 20% of Sleeve Gastrectomy patients achieved target with out medications. The relative success rate of surgery over medical therapy at reaching biochemical resolution of T2DM was quite large and highly significant. Similarly, reduction in FPG favored surgery with and 87 and 63 point reduction compared to 28. Likewise, TG decreased 45 and 32% after surgery compared to MT. There were no differences in LDL cholesterol between the 3 groups.There were no differences in the percent change in carotid intimal medial thickness at 3 years betweent the three groups.
1 Gastric Bypass vs Medical Therapy; 2 Sleeve vs Medical Therapy 10

11. Change in HbA1c Change in HbA1c (%)
Medical
Sleeve
Gastric Bypass
Change in HbA1c (%)
P<0.001
The next 4 graphs depict the time course of change in key endpoints after initiating therapy. This graph shows absolute change in HbA1C among the three groups. Yellow is IMT, Orange is Gastric Bypass and Blue is Sleeve gastrectomy. The absolute values are shown in the corresponding columns below each time period. After surgery there was dramatic and rapid reduction in HbA1c mostly in the first 3 months with a net reduction of nearly 3% at 12 months with persistent effects of 2.5% at 36 months. There was more gradual and modest improvement in A1c after MT which maximized at 6 months then began to relapse therafter with a net reduction of less than 1% at 36 months.
P<0.001

12. Change in Body Mass Index
Change in BMI (Kg/M2)
Medical
Sleeve
Gastric Bypass
P<0.001
P=0.006
This graph shows change in BMI among the three groups. After surgery there was a gradual and steady 9 and 10 point decrease in BMI. The decrease in BMI was modest in the medical group but yet this decrease is remarkable considering the high use of insulin and other potential weight gaining drugs. At 36 months there was greater weight loss in the gastric bypass vs. sleeve gastrectomy group.
P<0.001

13. Percentage of Patients on Insulin
Medical
Sleeve
Gastric Bypass
Insulin dependency is another important marker of disease severity. In this graph you can see that nearly one half of all patients at base line are using insulin. At 36 months virtually all patients in the surgery groups were weaned off Medical patients still required insulin. Even with this high insulin usage the medical patients had inferior glycemic control compared to the surgical patients.
Medical
Gastric Bypass
Sleeve

14. Cardiovascular Medications at Baseline and Month 36
CV medications – number (%)
Medical Therapy (n=40)
Bypass (n=48)
Sleeve (n=49)
Baseline
None
0 (0)
3 (6.3)
2 (4.1)
1 - 2
19 (47.5)
17 (35.4)
28 (57.1)
> 3
21 (52.5)
28 (58.3)
19 (38.8)
Month 36
1 (2.5)
33 (68.8) *
21 (42.9) *
18 (45)
14 (29.2)
25 (51)
1 (2.1)
3 (6.1)
This Table shows usage of CV medications such as antihypertensive agents, lipid lower agents, Beta blockers, Ca++ channel blockers, Ace inhibitors and diuretics after medical and surgical treatment. Although blood pressure and LDL Cholesterol did not change significantly in the 3 groups, there was a significant decrease in CV medications. At baseline, most patients were taking 2 or 3 or more CV medications. At 36 months,68% and 43% did not take any CV medications. The surgical patients experienced a significant decrease in dependency on both anti- diabetic drugs and CV drugs.
* P value <0.05 with Medical Therapy group as comparator 14

15. Quality of Life ** ** % * * <0.05 ** <0.001 ** * %
Physical Functioning
Role Limitations
Physical Health
Components
Mental Health ** ** % *
* < ** <0.001
(Compared to IMT) **
Several quality of life parameters measured by the SF 36 survey showed that surgery resulted in improved physical function, less body pain and improved overall general health. Increased energy were also noted in the surgical groups. * %

16. Adverse Events through 36 Months
Parameter
Medical Therapy (n=43)
Bypass (n=50)
Sleeve (n=49)
GI complications
2 (5)
13 (26)
5 (4)
Re-op
2(4)
Stroke
1 (2)
Retinopathy
2 (4)
Nephropathy
4 (9)
7 (14)
5 (10)
Foot ulcers
Excessive weight gain
7 (16)
This table shows key adverse events in all 3 treatment groups. As expected, greater GI complications occurred in the gastric bypass group with 4 reoperations required within the the forst 12 months. There were a few cases of diabetic complication noted in the surgical groups. Weight gain of greater than 5% occurred in 16% of the IMT 16

17. Limitations
Single-center trial – multicenter studies needed to determine if results can be generalized.
Larger studies will need to determine potential benefit on cardiovascular events and diabetes related microvascular complications.
This study does have limitations. This was a single center trial so multicenter studies are needed to determine if the results can be generalized. Finally, larger studies will need to determine whether these improvements in glycemic control and CV risk factors actually reduce CV events and/or end organ failure from microvascular disease.

18. Summary
Bariatric surgery was more effective than intensive medical therapy in achieving glycemic control (HbA1c < 6.0%) with weight loss as the primary determinant of this outcome.
Many surgical patients achieved glycemic control without use of any diabetic medications (particularly insulin).
Metabolic syndrome components (HDL, triglycerides, glucose, BMI) showed greater improvement after surgery.
Marked improvement in quality of life. 18

19. Conclusion
Bariatric surgery (gastric bypass or sleeve gastrectomy) should be considered as a treatment option for patients with uncontrolled T2DM and moderate to severe obesity (BMI > 30 Kg/M2) with results durable through 3 years of follow up.

20. Renal Outcomes through 36 Months