Diabetes Report UNPDF

PRELIMINARY

COMMUNICATION

Adjustable Gastric Banding and

Conventional Therapy for Type 2 Diabetes

A Randomized Controlled Trial

John B. Dixon, MBBS, PhD

Paul E. O’Brien, MD

Julie Playfair, RN

Leon Chapman, MBBS

Linda M. Schachter, MBBS, PhD

Stewart Skinner, MBBS, PhD

Joseph Proietto, MBBS, PhD

Michael Bailey, PhD, MSc(stats)

Margaret Anderson, BHealthMan

S IGNIFICANT SUSTAINED WEIGHT

Context Observational studies suggest that surgically induced loss of weight may

be effective therapy for type 2 diabetes.

Objective To determine if surgically induced weight loss results in better glycemic

control and less need for diabetes medications than conventional approaches to weight

loss and diabetes control.

Design, Setting, and Participants Unblinded randomized controlled trial con-

ducted from December 2002 through December 2006 at the University Obesity Re-

search Center in Australia, with general community recruitment to established treat-

ment programs. Participants were 60 obese patients (BMI 30 and 40) with recently

diagnosed ( 2 years) type 2 diabetes.

Interventions Conventional diabetes therapy with a focus on weight loss by life-

style change vs laparoscopic adjustable gastric banding with conventional diabetes

care.

Main Outcome Measures Remission of type 2 diabetes (fasting glucose level 126

mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA 1c ] value 6.2% while taking no

glycemic therapy). Secondary measures included weight and components of the meta-

bolic syndrome. Analysis was by intention-to-treat.

Results Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Re-

mission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%)

in the conventional-therapy group. Relative risk of remission for the surgical group

was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups

lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years

( P .001). Remission of type 2 diabetes was related to weight loss ( R 2 =0.46, P .001)

and lower baseline HbA 1c levels (combined R 2 =0.52, P .001). There were no serious

complications in either group.

Conclusions Participants randomized to surgical therapy were more likely to achieve

remission of type 2 diabetes through greater weight loss. These results need to be con-

firmed in a larger, more diverse population and have long-term efficacy assessed.

Trial Registration actr.org Identifier: ACTRN012605000159651

JAMA. 2008;299(3):316-323

loss achieved using bariatric sur-

gery has never been formally in-

vestigated as a treatment for

type 2 diabetes in obese participants.

Several observational studies suggest

substantial benefit, but these have gen-

erally been restricted to severely obese

participants; to our knowledge, there

have been no published randomized

controlled trials.

Obesity and type 2 diabetes are likely

to be the 2 greatest public health prob-

lems of the coming decades. 1 The con-

ditions are strongly linked, with the

increased prevalence of diabetes cor-

relating with the increased prevalence

of obesity. 2 The adjusted relative risk

of developing type 2 diabetes in par-

ticipants with a body mass index (BMI)

greater than 35 (calculated as weight in

kilograms divided by height in meters

squared) is 93 (95% confidence inter-

val [CI], 81-107) for women 3 and 42

(95% CI, 22-81) for men, 4 compared

www.jama.com

Author Affiliations: Centre for Obesity Research and

Education (Drs Dixon, O’Brien, Chapman, Schachter,

and Skinner and Mss Playfair and Anderson) and De-

partment of Epidemiology and Preventive Medicine

(Dr Bailey), Monash University, Melbourne, Austra-

lia; and Department of Medicine (AH/NH), Univer-

sity of Melbourne, Melbourne (Dr Proietto).

Corresponding Author: John B. Dixon, MBBS, PhD,

FRACGP, Centre for Obesity Research and Educa-

tion, Monash University Medical School, The Alfred

Hospital, Melbourne, Victoria, 3004, Australia (john

.dixon@med.monash.edu.au).

with participants with a BMI less than

22 and less than 23, respectively.

Approximately half of those diag-

nosed with type 2 diabetes are obese. 5

Early and intensive treatment of type

2 diabetes is known to improve health

outcomes and quality of life. 6-9 Weight

control comprises perhaps the most im-

For editorial comment see p 341.

316 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

portant aspect of type 2 diabetes man-

agement, with weight loss reducing

morbidity and mortality. 10 Recent evi-

dence indicates that improvement in

blood glucose control is related to de-

gree of weight loss. 11 Unfortunately,

currently available lifestyle and phar-

macological strategies provide only

small to modest levels of weight loss,

a problem compounded by patients

with diabetes experiencing greater dif-

ficulty in losing weight than those with-

out diabetes. 12-14 The costs associated

with medical weight loss therapies for

obese patients with type 2 diabetes are

high and ongoing. 15

Despite observational evidence sug-

gesting that weight-loss surgery is asso-

ciated with a 60% to 80% diabetes remis-

sion rate in severely obese persons and

that earlier interventions are more likely

to provide remission, 16 bariatric proce-

dures fail to generate significant atten-

tion in diabetes guidelines. 17 Concerns

exist regarding the lack of randomized

controlled evidence, as well as the safety,

invasiveness, and cost-effectiveness of

surgical weight loss procedures. Provid-

ing appropriate evidence has previ-

ously proved problematic, because the

invasive nature of the surgery makes par-

ticipant recruitment difficult. How-

ever, with the advent of safer, less inva-

sive surgical weight-loss procedures,

randomized controlled trials are now fea-

sible, and studies examining mild to

moderate obesity, which is responsible

for much of the diabetes burden, are pos-

sible.

Multiple case series have demon-

strated that laparoscopic adjustable

gastric banding (LAGB) results in sig-

nificant weight loss, 18-20 with medium-

term weight loss of approximately

20% of body weight 21 ; perioperative

mortality is approximately 0.05% for

LAGB. 21

Using the LAGB intervention, we

conducted a 2-year randomized con-

trolled trial involving 60 obese partici-

pants (BMI 30 and 40) to com-

pare surgically induced weight loss with

conventional therapy for the manage-

ment of recently diagnosed type 2 dia-

betes ( 2 years).

changes required to maximize cur-

rent management. A run-in period of

at least 3 months was undertaken in

which further alterations to eating,

exercise, glucose self-monitoring,

and medications were suggested.

During this time, study compliance

was assessed using attendance at

appointments and completion of

questionnaires. The endocrinologist

independently determined when a

patient was ready for randomization.

Baseline weight, blood pressure,

anthropometric measures, and bio-

chemical data (levels of fasting

plasma glucose, glycated hemoglobin

[HbA 1c ], C-peptide, and serum insu-

lin, and a lipid profile) were mea-

sured immediately prior to random-

ization.

STUDY DESIGN

Patient Recruitment

Patients were recruited via newspaper

advertisement and were not paid to par-

ticipate, nor did they pay any medical

costs. The study was reviewed and ap-

proved by the human ethics commit-

tees of The Alfred Hospital, The Av-

enue Hospital, and Monash University

in accordance with the guidelines of the

National Health and Medical Re-

search Council and the Helsinki Dec-

laration, as revised in 2000. Recruit-

ment commenced in December 2002,

the last participant was randomized in

November 2004, and all data were avail-

able for analysis in December 2006. All

participants provided written in-

formed consent to participate in the

study. Additional written informed con-

sent was obtained prior to any surgi-

cal procedure.

Randomization Process

Randomization was computer de-

rived, with blocking into 3 groups to

allow for orderly recruitment into both

study groups and to reduce the risk of

uneven recruitment late in the series.

The study was not blinded.

Inclusion Criteria

Patients were eligible if they were aged

between 20 and 60 years, had a body

mass index of 30 to 40, had been diag-

nosed with clearly documented type 2

diabetes within the previous 2 years,

had no evidence of renal impairment

or diabetic retinopathy, and were able

to understand and comply with the

study process.

Treatment Groups

Conventional-Therapy Program.

This program delivered best available

medical practice for the treatment,

education, and follow-up of patients

with type 2 diabetes. Patients had

open access to a general physician,

dietitian, nurse, and diabetes educator

and had visits with at least 1 team

member every 6 weeks throughout

the 2 years. Medical therapies, includ-

ing pharmaceutical agents, were deter-

mined by an experienced diabetolo-

gist on an individual basis.

Lifestyle modification programs were

individually structured to reduce en-

ergy intake, to reduce intake of fat

( 30%) and saturated fats, and to en-

courage intake of low glycemic index

and high-fiber foods. Physical activity

advice encouraged 10 000 steps per day

and 200 minutes per week of struc-

tured activity, including moderate-

intensity aerobic activity and resis-

tance exercise. Lifestyle was the primary

approach to weight loss, but very low-

Exclusion Criteria

Candidates were excluded if they had

a history of type 1 diabetes, diabetes

secondary to a specific disease, or pre-

vious bariatric surgery; a history of

medical problems such as mental

impairment, drug or alcohol addic-

tion, recent major vascular event,

internal malignancy, or portal hyper-

tension; or a contraindication for

either study group. Participants were

excluded if they did not attend 2 ini-

tial information visits.

Assessment and Run-in Period

In addition to any assessments re-

quired for inclusion, each potential

participant was assessed by a dieti-

tian, a general physician, and a con-

sultant endocrinologist specializing

in diabetes (L.C.) to suggest any

(Reprinted) JAMA, January 23, 2008—Vol 299, No. 3 317

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

Data Analysis. Univariate statisti-

cal analysis was performed using SPSS

version 12.01 (SPSS Inc, Chicago, Illi-

nois), with baseline comparisons made

using 2 tests for equal proportion,

t tests for normally distributed out-

comes, or Mann-Whitney U tests oth-

erwise. Multivariate longitudinal analy-

sis was performed to assess weight and

biochemical changes with time using

the PROC Mixed procedure in SAS ver-

sion 8.2 (SAS Institute Inc, Cary, North

Carolina). All data were analyzed using

a true intention-to-treat analysis for all

60 patients. Continuous variables were

expressed as mean (standard devia-

tion), with differences expressed as

mean (95% CI). Binary logistic regres-

sion was used to examine the associ-

ates of diabetes remission. A 2-sided

P value of .05 was considered statisti-

cally significant.

Primary and Secondary Outcomes

The primary end points of the study re-

lated to glycemic control at 2 years af-

ter randomization. These were as-

sessed as the proportion of participants

achieving remission (exceptional gly-

cemic control) of type 2 diabetes, de-

fined as fasting plasma glucose levels

less than 126 mg/dL (to convert to

mmol/L, multiply by 0.0555) in addi-

tion to HbA 1c values less than 6.2%

without the use of oral hypoglycemics

or insulin. The use of metformin posed

a dilemma, because it may be recom-

mended in the remitted diabetic state.

Our protocol recommended cessation

of metformin, if prescribed, when the

fasting insulin concentration was nor-

mal ( 17.0 uIU/mL [to convert to

pmol/L, multiply by 6.945]) and the

HbA 1c value was less than 6.2% with a

normal fasting plasma glucose level less

than 108.0 mg/dL.

Secondary outcome measures in-

cluded percentage change in HbA 1C lev-

els, weight, blood pressure, waist cir-

cumference, and levels of fasting lipids,

including total cholesterol, triglycer-

ides, and high-density lipoprotein cho-

lesterol. Changes in medication use,

changes in the proportion of partici-

pants with the metabolic syndrome as

defined by the National Cholesterol

Education Program Adult Treatment

Panel III criteria, 24 and changes in in-

direct measures of insulin resistance

using the homeostatic model assess-

ment method were assessed. Adverse

events and effects were recorded.

Figure 1. Participant Recruitment,

Assessment, and Participation Throughout

the Study

158 Individuals assessed

for eligibility by

telephone

25 Excluded after a

brief explanation of

the study

133 Underwent clinical

assessment

73 Excluded after clinical

assessment

10 BMI too high

1 BMI too low

7 Medical exclusions

3 Surgical exclusions

4 Diabetes diagnosed

> 2 years before

presentation

18 No diabetes

1 Outside age range

14 Did not return for

second clinical

interview

12 Refused

randomization

3 Geographical

distance precluded

involvement

RESULTS

Study Participants

The flow of participants through the

study is shown in F IGURE 1 . One pa-

tient randomized to surgery withdrew

from the study on the evening prior to

scheduled operation and did not agree

to be further followed up. The remain-

ing 29 surgically treated patients (97%)

completed the 2-year program. Of the

conventionally treated patients, 26

(87%) completed the 2-year assess-

ment. The baseline characteristics of the

groups are shown in T ABLE 1 . There

were no statistically significant differ-

ences in demographics or values con-

tributing to study outcomes between

the groups. There were only 13 partici-

pants with a baseline BMI less than

35—6 randomized to surgery and 7 to

the conventional-therapy group. The

mean BMI of those recruited to the

study was 37.1.

All bands were placed laparoscopi-

cally, with a mean procedure time of

54 minutes (SD, 10.8; range, 40-74),

and hospital admissions lengths were

1 day (23 [80%]), 2 days (5 [17%]),

and 4 days (1 [3%]). The patient

who stayed 4 days had the band

removed on day 15 due to band

intolerance. This patient underwent

60 Randomized

30 Randomized to receive

surgical treatment

30 Randomized to receive

conventional treatment

1 Withdrew preoperatively

4 Withdrew

3 Withdrew within

first month after

randomization

1 Withdrew 4 months

after randomization

29 Completed the study

26 Completed the study

30 Included in analysis

BMI indicates body mass index.

calorie diets and medications were dis-

cussed with all patients and used after

consultation with the dietitian or gen-

eral physician if the patient expressed

a desire to use additional measures.

Surgical Program. In addition to all

aspects of the conventional-therapy pro-

gram, the surgical group underwent

placement of a laparoscopic adjust-

able gastric band via the pars flaccida

technique by 1 of 2 experienced sur-

geons within 1 month of randomiza-

tion. 22 Progress was reviewed by the bar-

iatric surgical team every 4 to 6 weeks

throughout the study, and adjust-

ments to band volume were made using

standard clinical criteria. 23

Statistical Analysis

Sample Size. Sample size was selected

to provide a statistical power of 80% to

detect a 1% difference in HbA 1c values

between the groups at 2 years (group

mean, 6.5% vs 7.5% [SD, 1.3%])

( P .05). 25 The study was also pow-

ered for diabetes remission rates on the

basis that we expected approximately

60% remission in the surgical group and

20% in the conventional-therapy

group. 25 To allow for these scenarios,

a minimum of 27 patients were re-

quired in each study group. Recruit-

ment size was therefore set at 60.

318 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

PRELIMINARY

COMMUNICATION

Adjustable Gastric Banding and

Conventional Therapy for Type 2 Diabetes

A Randomized Controlled Trial

John B. Dixon, MBBS, PhD

Paul E. O’Brien, MD

Julie Playfair, RN

Leon Chapman, MBBS

Linda M. Schachter, MBBS, PhD

Stewart Skinner, MBBS, PhD

Joseph Proietto, MBBS, PhD

Michael Bailey, PhD, MSc(stats)

Margaret Anderson, BHealthMan

S IGNIFICANT SUSTAINED WEIGHT

Context Observational studies suggest that surgically induced loss of weight may

be effective therapy for type 2 diabetes.

Objective To determine if surgically induced weight loss results in better glycemic

control and less need for diabetes medications than conventional approaches to weight

loss and diabetes control.

Design, Setting, and Participants Unblinded randomized controlled trial con-

ducted from December 2002 through December 2006 at the University Obesity Re-

search Center in Australia, with general community recruitment to established treat-

ment programs. Participants were 60 obese patients (BMI 30 and 40) with recently

diagnosed ( 2 years) type 2 diabetes.

Interventions Conventional diabetes therapy with a focus on weight loss by life-

style change vs laparoscopic adjustable gastric banding with conventional diabetes

care.

Main Outcome Measures Remission of type 2 diabetes (fasting glucose level 126

mg/dL [7.0 mmol/L] and glycated hemoglobin [HbA 1c ] value 6.2% while taking no

glycemic therapy). Secondary measures included weight and components of the meta-

bolic syndrome. Analysis was by intention-to-treat.

Results Of the 60 patients enrolled, 55 (92%) completed the 2-year follow-up. Re-

mission of type 2 diabetes was achieved by 22 (73%) in the surgical group and 4 (13%)

in the conventional-therapy group. Relative risk of remission for the surgical group

was 5.5 (95% confidence interval, 2.2-14.0). Surgical and conventional-therapy groups

lost a mean (SD) of 20.7% (8.6%) and 1.7% (5.2%) of weight, respectively, at 2 years

( P .001). Remission of type 2 diabetes was related to weight loss ( R 2 =0.46, P .001)

and lower baseline HbA 1c levels (combined R 2 =0.52, P .001). There were no serious

complications in either group.

Conclusions Participants randomized to surgical therapy were more likely to achieve

remission of type 2 diabetes through greater weight loss. These results need to be con-

firmed in a larger, more diverse population and have long-term efficacy assessed.

Trial Registration actr.org Identifier: ACTRN012605000159651

JAMA. 2008;299(3):316-323

loss achieved using bariatric sur-

gery has never been formally in-

vestigated as a treatment for

type 2 diabetes in obese participants.

Several observational studies suggest

substantial benefit, but these have gen-

erally been restricted to severely obese

participants; to our knowledge, there

have been no published randomized

controlled trials.

Obesity and type 2 diabetes are likely

to be the 2 greatest public health prob-

lems of the coming decades. 1 The con-

ditions are strongly linked, with the

increased prevalence of diabetes cor-

relating with the increased prevalence

of obesity. 2 The adjusted relative risk

of developing type 2 diabetes in par-

ticipants with a body mass index (BMI)

greater than 35 (calculated as weight in

kilograms divided by height in meters

squared) is 93 (95% confidence inter-

val [CI], 81-107) for women 3 and 42

(95% CI, 22-81) for men, 4 compared

www.jama.com

Author Affiliations: Centre for Obesity Research and

Education (Drs Dixon, O’Brien, Chapman, Schachter,

and Skinner and Mss Playfair and Anderson) and De-

partment of Epidemiology and Preventive Medicine

(Dr Bailey), Monash University, Melbourne, Austra-

lia; and Department of Medicine (AH/NH), Univer-

sity of Melbourne, Melbourne (Dr Proietto).

Corresponding Author: John B. Dixon, MBBS, PhD,

FRACGP, Centre for Obesity Research and Educa-

tion, Monash University Medical School, The Alfred

Hospital, Melbourne, Victoria, 3004, Australia (john

.dixon@med.monash.edu.au).

with participants with a BMI less than

22 and less than 23, respectively.

Approximately half of those diag-

nosed with type 2 diabetes are obese. 5

Early and intensive treatment of type

2 diabetes is known to improve health

outcomes and quality of life. 6-9 Weight

control comprises perhaps the most im-

For editorial comment see p 341.

316 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

portant aspect of type 2 diabetes man-

agement, with weight loss reducing

morbidity and mortality. 10 Recent evi-

dence indicates that improvement in

blood glucose control is related to de-

gree of weight loss. 11 Unfortunately,

currently available lifestyle and phar-

macological strategies provide only

small to modest levels of weight loss,

a problem compounded by patients

with diabetes experiencing greater dif-

ficulty in losing weight than those with-

out diabetes. 12-14 The costs associated

with medical weight loss therapies for

obese patients with type 2 diabetes are

high and ongoing. 15

Despite observational evidence sug-

gesting that weight-loss surgery is asso-

ciated with a 60% to 80% diabetes remis-

sion rate in severely obese persons and

that earlier interventions are more likely

to provide remission, 16 bariatric proce-

dures fail to generate significant atten-

tion in diabetes guidelines. 17 Concerns

exist regarding the lack of randomized

controlled evidence, as well as the safety,

invasiveness, and cost-effectiveness of

surgical weight loss procedures. Provid-

ing appropriate evidence has previ-

ously proved problematic, because the

invasive nature of the surgery makes par-

ticipant recruitment difficult. How-

ever, with the advent of safer, less inva-

sive surgical weight-loss procedures,

randomized controlled trials are now fea-

sible, and studies examining mild to

moderate obesity, which is responsible

for much of the diabetes burden, are pos-

sible.

Multiple case series have demon-

strated that laparoscopic adjustable

gastric banding (LAGB) results in sig-

nificant weight loss, 18-20 with medium-

term weight loss of approximately

20% of body weight 21 ; perioperative

mortality is approximately 0.05% for

LAGB. 21

Using the LAGB intervention, we

conducted a 2-year randomized con-

trolled trial involving 60 obese partici-

pants (BMI 30 and 40) to com-

pare surgically induced weight loss with

conventional therapy for the manage-

ment of recently diagnosed type 2 dia-

betes ( 2 years).

changes required to maximize cur-

rent management. A run-in period of

at least 3 months was undertaken in

which further alterations to eating,

exercise, glucose self-monitoring,

and medications were suggested.

During this time, study compliance

was assessed using attendance at

appointments and completion of

questionnaires. The endocrinologist

independently determined when a

patient was ready for randomization.

Baseline weight, blood pressure,

anthropometric measures, and bio-

chemical data (levels of fasting

plasma glucose, glycated hemoglobin

[HbA 1c ], C-peptide, and serum insu-

lin, and a lipid profile) were mea-

sured immediately prior to random-

ization.

STUDY DESIGN

Patient Recruitment

Patients were recruited via newspaper

advertisement and were not paid to par-

ticipate, nor did they pay any medical

costs. The study was reviewed and ap-

proved by the human ethics commit-

tees of The Alfred Hospital, The Av-

enue Hospital, and Monash University

in accordance with the guidelines of the

National Health and Medical Re-

search Council and the Helsinki Dec-

laration, as revised in 2000. Recruit-

ment commenced in December 2002,

the last participant was randomized in

November 2004, and all data were avail-

able for analysis in December 2006. All

participants provided written in-

formed consent to participate in the

study. Additional written informed con-

sent was obtained prior to any surgi-

cal procedure.

Randomization Process

Randomization was computer de-

rived, with blocking into 3 groups to

allow for orderly recruitment into both

study groups and to reduce the risk of

uneven recruitment late in the series.

The study was not blinded.

Inclusion Criteria

Patients were eligible if they were aged

between 20 and 60 years, had a body

mass index of 30 to 40, had been diag-

nosed with clearly documented type 2

diabetes within the previous 2 years,

had no evidence of renal impairment

or diabetic retinopathy, and were able

to understand and comply with the

study process.

Treatment Groups

Conventional-Therapy Program.

This program delivered best available

medical practice for the treatment,

education, and follow-up of patients

with type 2 diabetes. Patients had

open access to a general physician,

dietitian, nurse, and diabetes educator

and had visits with at least 1 team

member every 6 weeks throughout

the 2 years. Medical therapies, includ-

ing pharmaceutical agents, were deter-

mined by an experienced diabetolo-

gist on an individual basis.

Lifestyle modification programs were

individually structured to reduce en-

ergy intake, to reduce intake of fat

( 30%) and saturated fats, and to en-

courage intake of low glycemic index

and high-fiber foods. Physical activity

advice encouraged 10 000 steps per day

and 200 minutes per week of struc-

tured activity, including moderate-

intensity aerobic activity and resis-

tance exercise. Lifestyle was the primary

approach to weight loss, but very low-

Exclusion Criteria

Candidates were excluded if they had

a history of type 1 diabetes, diabetes

secondary to a specific disease, or pre-

vious bariatric surgery; a history of

medical problems such as mental

impairment, drug or alcohol addic-

tion, recent major vascular event,

internal malignancy, or portal hyper-

tension; or a contraindication for

either study group. Participants were

excluded if they did not attend 2 ini-

tial information visits.

Assessment and Run-in Period

In addition to any assessments re-

quired for inclusion, each potential

participant was assessed by a dieti-

tian, a general physician, and a con-

sultant endocrinologist specializing

in diabetes (L.C.) to suggest any

(Reprinted) JAMA, January 23, 2008—Vol 299, No. 3 317

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

Data Analysis. Univariate statisti-

cal analysis was performed using SPSS

version 12.01 (SPSS Inc, Chicago, Illi-

nois), with baseline comparisons made

using 2 tests for equal proportion,

t tests for normally distributed out-

comes, or Mann-Whitney U tests oth-

erwise. Multivariate longitudinal analy-

sis was performed to assess weight and

biochemical changes with time using

the PROC Mixed procedure in SAS ver-

sion 8.2 (SAS Institute Inc, Cary, North

Carolina). All data were analyzed using

a true intention-to-treat analysis for all

60 patients. Continuous variables were

expressed as mean (standard devia-

tion), with differences expressed as

mean (95% CI). Binary logistic regres-

sion was used to examine the associ-

ates of diabetes remission. A 2-sided

P value of .05 was considered statisti-

cally significant.

Primary and Secondary Outcomes

The primary end points of the study re-

lated to glycemic control at 2 years af-

ter randomization. These were as-

sessed as the proportion of participants

achieving remission (exceptional gly-

cemic control) of type 2 diabetes, de-

fined as fasting plasma glucose levels

less than 126 mg/dL (to convert to

mmol/L, multiply by 0.0555) in addi-

tion to HbA 1c values less than 6.2%

without the use of oral hypoglycemics

or insulin. The use of metformin posed

a dilemma, because it may be recom-

mended in the remitted diabetic state.

Our protocol recommended cessation

of metformin, if prescribed, when the

fasting insulin concentration was nor-

mal ( 17.0 uIU/mL [to convert to

pmol/L, multiply by 6.945]) and the

HbA 1c value was less than 6.2% with a

normal fasting plasma glucose level less

than 108.0 mg/dL.

Secondary outcome measures in-

cluded percentage change in HbA 1C lev-

els, weight, blood pressure, waist cir-

cumference, and levels of fasting lipids,

including total cholesterol, triglycer-

ides, and high-density lipoprotein cho-

lesterol. Changes in medication use,

changes in the proportion of partici-

pants with the metabolic syndrome as

defined by the National Cholesterol

Education Program Adult Treatment

Panel III criteria, 24 and changes in in-

direct measures of insulin resistance

using the homeostatic model assess-

ment method were assessed. Adverse

events and effects were recorded.

Figure 1. Participant Recruitment,

Assessment, and Participation Throughout

the Study

158 Individuals assessed

for eligibility by

telephone

25 Excluded after a

brief explanation of

the study

133 Underwent clinical

assessment

73 Excluded after clinical

assessment

10 BMI too high

1 BMI too low

7 Medical exclusions

3 Surgical exclusions

4 Diabetes diagnosed

> 2 years before

presentation

18 No diabetes

1 Outside age range

14 Did not return for

second clinical

interview

12 Refused

randomization

3 Geographical

distance precluded

involvement

RESULTS

Study Participants

The flow of participants through the

study is shown in F IGURE 1 . One pa-

tient randomized to surgery withdrew

from the study on the evening prior to

scheduled operation and did not agree

to be further followed up. The remain-

ing 29 surgically treated patients (97%)

completed the 2-year program. Of the

conventionally treated patients, 26

(87%) completed the 2-year assess-

ment. The baseline characteristics of the

groups are shown in T ABLE 1 . There

were no statistically significant differ-

ences in demographics or values con-

tributing to study outcomes between

the groups. There were only 13 partici-

pants with a baseline BMI less than

35—6 randomized to surgery and 7 to

the conventional-therapy group. The

mean BMI of those recruited to the

study was 37.1.

All bands were placed laparoscopi-

cally, with a mean procedure time of

54 minutes (SD, 10.8; range, 40-74),

and hospital admissions lengths were

1 day (23 [80%]), 2 days (5 [17%]),

and 4 days (1 [3%]). The patient

who stayed 4 days had the band

removed on day 15 due to band

intolerance. This patient underwent

60 Randomized

30 Randomized to receive

surgical treatment

30 Randomized to receive

conventional treatment

1 Withdrew preoperatively

4 Withdrew

3 Withdrew within

first month after

randomization

1 Withdrew 4 months

after randomization

29 Completed the study

26 Completed the study

30 Included in analysis

BMI indicates body mass index.

calorie diets and medications were dis-

cussed with all patients and used after

consultation with the dietitian or gen-

eral physician if the patient expressed

a desire to use additional measures.

Surgical Program. In addition to all

aspects of the conventional-therapy pro-

gram, the surgical group underwent

placement of a laparoscopic adjust-

able gastric band via the pars flaccida

technique by 1 of 2 experienced sur-

geons within 1 month of randomiza-

tion. 22 Progress was reviewed by the bar-

iatric surgical team every 4 to 6 weeks

throughout the study, and adjust-

ments to band volume were made using

standard clinical criteria. 23

Statistical Analysis

Sample Size. Sample size was selected

to provide a statistical power of 80% to

detect a 1% difference in HbA 1c values

between the groups at 2 years (group

mean, 6.5% vs 7.5% [SD, 1.3%])

( P .05). 25 The study was also pow-

ered for diabetes remission rates on the

basis that we expected approximately

60% remission in the surgical group and

20% in the conventional-therapy

group. 25 To allow for these scenarios,

a minimum of 27 patients were re-

quired in each study group. Recruit-

ment size was therefore set at 60.

318 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from

cant ( P =.005) reduction in use of

antihypertensive agents in the surgi-

cal group (20/29 at baseline and 6/29

at 2 years, P .001) compared with the

conventional-therapy group (15/26 at

baseline and at 2 years). There also

was a reduction in the use of lipid-

lowering medications in the surgical

group (12/29 at baseline and 4/29 at 2

years, P =.02) but no significant change

in the conventional-therapy group (8/26

at baseline and 7/26 at 2 years).

Figure 2. Percentage of Weight Loss Achieved Over the 2-Year Study Period (n=60) and

Individual Weight Measures at Baseline and at 2 Years

Surgical group

Achieved remission

of type 2 diabetes

Did not achieve remission

of type 2 diabetes

Conventional group

Achieved remission

of type 2 diabetes

Did not achieve remission

of type 2 diabetes

Change in Weight

Percent Weight Change

160

140

–10

120

Adverse Events

Surgical Group. One patient devel-

oped a superficial wound infection over

the access port site 2 weeks postplace-

ment, which resolved with intravenous

antibiotics. Two patients developed gas-

tric pouch enlargement, both at 10

months after placement, and were

treated with nonurgent laparoscopic re-

visional surgery to remove and replace

the band. One patient experienced eat-

ing difficulties and persistent regurgita-

tion with no saline in the band and no

impedance of flow on contrast study. The

band was removed 15 days after place-

ment. Hospital stay for each revisional

procedure was less than 1 day, and there

were no complications. Other adverse

events reported were postoperative fe-

brile episodes in 1 patient. No cause was

found, and the fever resolved. A minor

hypoglycemic episode occurred in 1 pa-

tient and gastrointestinal tract intoler-

ance to metformin in another.

Conventional-Therapy Group. Tw o

patients had minor gastrointestinal tract

adverse effects, and 1 had persistent di-

arrhea with metformin. One patient de-

veloped vasculitic rash, possibly re-

lated to rosiglitazone. All problems

resolved when the medications were

discontinued. One patient had mul-

tiple hypoglycemic episodes, and an-

other was admitted to hospital with an-

gina and a transient cerebral ischemic

episode. Two patients were intolerant

of very low-calorie meal replacement.

–20

100

–30

–40

–50

Surgical

Group

Conventional

Group

Baseline

Ye a r s

Baseline

Ye a r s

Surgical Group

Conventional Group

Remission indicates those achieving remission of type 2 diabetes (see “Methods”) at 2 years. Data markers

with error bars indicate mean (SD).

6.2%; at 2 years, the numbers were 24

(80%) and 6 (20%), respectively. The

proportion with HbA 1c levels less than

6.2% improved significantly

( P .001) in the surgical group but

not in the conventional-therapy

group.

Other Health Outcomes

T ABLE 2 shows changes in some clini-

cal and laboratory measures of health

at 24 months. The surgical group had

a significantly greater improvement at

2 years in insulin resistance and in lev-

els of triglycerides and high-density li-

poprotein cholesterol. The metabolic

syndrome was present in 29 patients

(97%) in each group prior to com-

mencement of treatment, and 21 (70%)

of surgically treated and 4 (13%) con-

ventionally treated participants did not

fulfill the National Cholesterol Educa-

tion Program Adult Treatment Panel III

criteria at 2 years ( P .001). The re-

duction in the metabolic syndrome was

significant in the surgical group

( P .001) but not in the conventional-

therapy group ( P =.23). Caution is re-

quired in interpreting these results, as

the study was not powered to assess

multiple outcome measures.

Use of Diabetes Medication

There was a significant reduction in the

use of pharmacotherapy for glycemic

control in the surgical group at 2 years.

At baseline, 2 surgically treated and 4

conventionally treated patients were not

using pharmacotherapy; at 2 years, the

numbers were 26 and 8, respectively.

In the surgical group at 2 years there

were fewer using metformin (3 vs 28,

P .001) and other hypoglycemic

therapy (1 vs 9, P =.006). The 1 surgi-

cal patient using insulin at baseline was

in remission at 2 years. There were no

significant changes in the use of therapy

in the group randomized to receive con-

ventional therapy. Metformin was used

by 26 and 18, other oral hypoglyce-

mic agents by 8 and 7, and insulin by

0 and 3, at baseline and 2 years, respec-

tively.

Use of Nondiabetes Medication

Although there was no significant blood

pressure difference between com-

pleters in the surgical and conventional-

therapy groups, there was a signifi-

COMMENT

This study, to our knowledge the first

randomized trial comparing surgi-

cally induced loss of weight with con-

320 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

ventional therapy for management of

type 2 diabetes in obese participants,

demonstrates superior glycemic con-

trol and diabetes remission rates with

adjustable gastric banding. After 2 years,

the surgical group displayed a 5 times

higher remission rate and 4 times

greater reduction in HbA 1c values than

the conventional-therapy group. This

study confirms the findings of several

observational studies, 25,27-30 including

the case-controlled Swedish Obese Sub-

jects Study, 31 that found heightened dia-

betes remission rates among 2000 pa-

tients undergoing gastric stapling with

follow-up for 10 years.

In addition to superior glycemic con-

trol, this study also demonstrates higher

rates of resolution of the metabolic syn-

drome, confirming the finding of an ear-

lier randomized controlled trial, 32 as

well as improvements in insulin sensi-

tivity and concentrations of triglycer-

ides and high-density lipoprotein cho-

lesterol in the surgical group. These

changes in secondary outcome mea-

sures need to be examined with cau-

tion and are hypothesis-generating only,

as the study was not powered for an ex-

amination of multiple secondary out-

come measures. There also appeared to

be significant reductions in the use of

oral hypoglycemic, antihypertensive,

and lipid-lowering medications in pa-

tients randomized to surgery. Al-

though the physician responsible for al-

tering medications was not blinded to

treatment group, blood pressure and

biochemical data indicate that decision-

making was determined by clinical

need.

An important finding of this study is

that degree of weight loss, not the

method, appears to be the major driver

of glycemic improvement and diabe-

tes remission in obese participants. This

has important implications, as it sug-

gests that intensive weight-loss therapy

may be a more effective first step in the

management of diabetes than simple

lifestyle change. This study shows that

few participants achieved remission

with a body weight loss of less than

10%, a level expected to produce im-

portant health benefits. 33

The aim of this current trial was to

compare 2 established treatment pro-

grams that involve widely available and

accepted therapies. The use of bariatric

surgery is rapidly increasing, and more

than 90% of procedures performed in

Australia are LAGB. At the time this

study was carried out, early intensive use

of insulin was unusual practice in Aus-

tralia, and access to thiozoladinedione

medications was restricted for patients

with poor glycemic control. The hypo-

glycemic agent exenatide was also un-

available. The results achieved by the

surgical group in this study closely re-

semble those now being targeted by ex-

perimental intensive medical therapies

using multiple hypoglycemic strate-

gies, including exenatide and early in-

sulin use. 34 It is worth noting that the

results achieved by weight-loss surgery

come without the risks of hypoglyce-

mia and weight gain often associated

with medical therapies.

Table 2. Primary and Secondary Outcomes at 2 Years a

Mean (SD)

Between-Group

Difference,

Mean (95% CI)

Surgery

(n = 30)

Conventional

Therapy (n = 30)

Primary Outcome, No. (%)

Value

Variable

Remission of diabetes,

No. (%)

22 (73)

4 (13)

RR for surgical

remission,

5.5 (2.2 to 14.0)

.001

Secondary Outcomes

Weight, kg

84.6 (15.8)

104.8 (15.3)

Change, kg

−21.1 (10.5)

−1.5 (5.4)

−19.6 (−23.8 to −15.2)

.001

Waist circumference, cm

95.8 (10.3)

112.7 (10.3)

Change, cm

−17.9 (10.8)

−4.0 (9.1)

−13.9 (−19.0 to −8.7)

.001

Waist to hip ratio

0.90 (0.06)

0.95 (0.08)

Change

−0.06 (0.06)

−0.01 (0.06)

−0.05 (−0.07 to −0.007)

.02

Blood pressure, mm Hg

Systolic

130.4 (19.0)

132.6 (17.7)

Change

−6.0 (17.9)

−1.7 (14.2)

−4.3 (−13.6 to 5.1)

.37

Diastolic

85.4 (7.0)

83.1 (8.5)

Change

−0.7 (11.1)

−0.9 (11.1)

0.2 (−5.4 to 6.0)

.92

HbA 1c , %

6.00 (0.82)

7.21 (1.39)

Change

−1.81 (1.24)

−0.38 (1.26)

−1.43 (−2.1 to −0.80)

.001

Plasma glucose, mg/dL

105.6 (30.3)

139.6 (38.1)

Change

−51.2 (37.6)

−18.4 (41.2)

−32.8 (−53.1 to −12.3)

.002

Plasma insulin, µIU/mL

9.8 (4.7)

24.1 (13.6)

Change

−12.4 (8.4)

1.0 (14.8)

−13.4 (−19.6 to −7.3)

.001

HOMA IR b

1.90 (0.73)

3.50 (0.97)

Change, %

−45.5 (19.0)

−3.3 (35.4)

−42.2 (−57 to −26.8) c

.001

Total cholesterol, mg/dL

205.4 (46.6)

197.8 (59.3)

Change

3.6 (51.6)

−0.4 (31.4)

4.0 (−18.8 to 26.0)

.72

Triglycerides, mg/dL

118.9 (79.7)

186.7 (127.2)

Change

−71.7 (92.9)

−2.1 (120.6)

−69.6 (−125.3 to −13.6)

.02

HDL-C, mg/dL

59.7 (13.6)

50.7 (12.1)

Change

12.6 (9.8)

2.6 (6.1)

10.0 (5.8 to 14.2)

.001

Total cholesterol to

HDL-C ratio

3.58 (1.00)

4.1 (1.4)

Change −0.82 (1.9) −0.14 (1.04) −0.68 (−1.24 to −0.14) .02

Abbreviations: CI, confidence interval; HbA 1c , glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA

IR, insulin resistance by homeostatic model assessment; LDL-C, low-density lipoprotein cholesterol; RR, relative risk.

SI conversion factors: see Table 1 footnote.

a Mean (SD) percentage change for participants with baseline values carried forward for those who dropped out of the

study. A comparison of the actual change from baseline is also presented. Data include all 60 participants with base-

line data carried forward for missing data.

b An indirect measure of insulin resistance calculated from levels of fasting plasma glucose and fasting C-peptide. 26

c P .05 calculated using independent t test.

(Reprinted) JAMA, January 23, 2008—Vol 299, No. 3 321

Downloaded from

ADJUSTABLE GASTRIC BANDING AND CONVENTIONAL THERAPY FOR TYPE 2 DIABETES

Importantly, this study is the first, to

our knowledge, to formally document

change in glycemic control in patients

with diabetes and BMI of 30 to 35 fol-

lowing surgically induced weight loss.

Bariatric surgical guidelines include

only BMI greater than 35 with comor-

bid type 2 diabetes as an indication for

weight loss surgery. 35,36 In this study we

found the benefits of weight loss as ef-

ficacious for participants with BMI in

the 30 to 35 range as for those with BMI

in the 35 to 40 range; however, analy-

sis and conclusions are limited, as there

were only 13 participants (22%) in this

BMI category.

Our study did not include partici-

pants with a BMI greater that 40. We

believed it inappropriate to recruit those

with a BMI greater than 40 into the

study, because a number of observa-

tional studies have shown effective-

ness of bariatric surgery in these pa-

tients.

The adverse events observed in this

trial were in line with expectations.

Among patients undergoing LAGB sur-

gery, rates of postoperative wound in-

fection around the port were approxi-

mately 1% to 2%, and reoperation rates

for gastric pouch enlargement were ap-

proximately 5%.

Several limitations of our study need

to be recognized. First, we restricted the

study to participants with a recent di-

agnosis ( 2 years) of type 2 diabetes,

and therefore results may not apply to

those with a longer history of disease

due to deterioration of -cell function

with time. Second, the experience of our

bariatric surgical team with the LAGB

procedure is extensive. Systematic re-

view shows inverse correlation be-

tween the experience of the LAGB sur-

gical team and incidence of early and

late complications. 21 Third, our study

was not powered for safety or to de-

tect differences in hard end points, such

as mortality or cardiovascular events.

Such studies would require many more

participants followed up over a much

longer period. Our study only fol-

lowed up participants for 2 years, and

results cannot be readily extrapolated

for longer periods. Clearly, weight re-

gain or simply the passage of time puts

those achieving remission of type 2 dia-

betes at risk of relapsing back into dia-

betic status.

One patient from the surgical group

and 4 from the conventional-therapy

group did not complete the 2-year fol-

low-up. To account for this missing in-

formation, the most conservative case

scenario was considered, with the 4

noncompleters from the conventional-

therapy group assumed to have

achieved diabetic remission and the

noncompleter from the surgical group

assumed to have not achieved remis-

sion. Under this scenario, the differ-

ence between the surgical and the con-

ventional-therapy groups for those

achieving remission still remained

highly significant (22/30 [73%] for sur-

gery vs 8/30 [27%] for conventional

therapy, P .001).

In conclusion, this randomized trial

demonstrates that weight loss associ-

ated with adjustable gastric banding re-

sults in diabetes remission in the ma-

jority of obese participants recently

diagnosed as having diabetes and was

associated with greater improvements

in features of the metabolic syndrome

and use of related medications. While

caution is required in interpreting the

longer-term benefits of surgery and

weight loss, this study presents strong

evidence to support the early consid-

eration of surgically induced loss of

weight in the treatment of obese pa-

tients with type 2 diabetes.

Medical Research Council, Allergan Health, and Novar-

tis Australia; having received compensation for serv-

ing on the speakers panel of Novartis Australia and

Allergan Health; and serving on the medical advisory

board of Novartis Australia and Allergan Health. Dr

O’Brien reported receiving research grants from the

National Health and Medical Research Council, Aller-

gan Health, and Novartis Australia; having received

compensation for serving on the speakers panel of Al-

lergan Health; and serving on the medical advisory

board of Allergan Health. Dr Chapman reported re-

ceiving travel grants and honoraria from Eli Lilly, Novo

Nordisc, Sanofi Aventis, and Alphapharm. Dr Proi-

etto reported serving on the medical advisory boards

of Novartis Australia, Eli Lilly Australia, Abbott Aus-

tralia, and Sanofi-Aventis Australia. No other disclo-

sures were reported.

Funding/Support: This study was funded by Monash

University, which has received an unrestricted grant

from Allergan Health. The laparoscopic adjustable gas-

tric bands (Allergan Health) and the laparoscopic ports

(Applied Medical) were provided without charge by

the manufacturers.

Role of the Sponsors: Allergan Health and Applied

Medical had no role in the design and conduct of the

study; the collection, analysis, and interpretation of

the data; or the preparation, review, or approval of

the manuscript.

REFERENCES

1. Zimmet P, Alberti KG, Shaw J. Global and societal

implications of the diabetes epidemic. Nature . 2001;

414(6865):782-787.

2. Mokdad AH, Ford ES, Bowman BA, et al. Diabe-

tes trends in the U.S.: 1990-1998. Diabetes Care . 2000;

23(9):1278-1283.

3. Colditz GA, Willett WC, Rotnitzky A, Manson JE.

Weight gain as a risk factor for clinical diabetes melli-

tus in women. Ann Intern Med . 1995;122(7):481-

486.

4. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Wil-

lett WC. Obesity, fat distribution, and weight gain as

risk factors for clinical diabetes in men. Diabetes Care .

1994;17(9):961-969.

5. Leibson CL, Williamson DF, Melton LJ III, et al. Tem-

poral trends in BMI among adults with diabetes. Dia-

betes Care . 2001;24(9):1584-1589.

6. UK Prospective Diabetes Study Group. UK pro-

spective diabetes study 16: overview of 6 years’ therapy

of type II diabetes: a progressive disease [published

correction appears in Diabetes . 1996;45(11):1655].

Diabetes . 1995;44(11):1249-1258.

7. UK Prospective Diabetes Study (UKPDS) Group. In-

tensive blood-glucose control with sulphonylureas or

insulin compared with conventional treatment and risk

of complications in patients with type 2 diabetes (UK-

PDS 33). Lancet . 1998;352(9131):837-853.

8. UK Prospective Diabetes Study Group. Quality of

life in type 2 diabetic patients is affected by compli-

cations but not by intensive policies to improve blood

glucose or blood pressure control (UKPDS 37). Dia-

betes Care . 1999;22(7):1125-1136.

9. UK Prospective Diabetes Study Group. Tight blood

pressure control and risk of macrovascular and micro-

vascular complications in type 2 diabetes: UKPDS 38

[published correction appears in BMJ .

1999;318(7175):29]. BMJ . 1998;317(7160):703-

713.

10. Williamson DF, Thompson TJ, Thun M, Flanders

D, Pamuk E, Byers T. Intentional weight loss and mor-

tality among overweight individuals with diabetes. Dia-

betes Care . 2000;23(10):1499-1504.

11. Norris SL, Zhang X, Avenell A, et al. Long-term

effectiveness of lifestyle and behavioral weight loss in-

terventions in adults with type 2 diabetes: a

meta-analysis. Am J Med . 2004;117(10):762-774.

12. Khan MA, St Peter JV, Breen GA, Hartley GG, Ves-

Author Contributions: Drs Dixon and Bailey and Ms

Anderson had full access to all of the data in the study

and take responsibility for the integrity of the data and

the accuracy of the data analysis.

Study concept and design: Dixon, O’Brien, Schachter,

Proietto.

Acquisition of data: Dixon, O’Brien, Playfair, Chapman,

Schachter, Skinner, Anderson.

Analysis and interpretation of data: Dixon, O’Brien,

Playfair, Bailey, Anderson.

Drafting of the manuscript: Dixon, O’Brien.

Critical revision of the manuscript for important in-

tellectual content: Dixon, O’Brien, Playfair, Chapman,

Schachter, Skinner, Proietto, Bailey, Anderson.

Statistical analysis: Dixon, Bailey, Anderson.

Obtained funding: Dixon, O’Brien.

Administrative, technical, or material support: Dixon,

O’Brien, Playfair, Schachter, Skinner, Proietto,

Anderson.

Study supervision: Dixon, O’Brien, Schachter,

Anderson.

Financial Disclosures: Dr Dixon reported having re-

ceived r esearch grants from the National Health and

322 JAMA, January 23, 2008—Vol 299, No. 3 (Reprinted)

Downloaded from