Surgery – cure of type 2 diabetes? -...

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Surgery – cure of type 2 diabetes?

Lena CarlssonThe Sahlgrenska AcademyGothenburgSweden

Swedish Obese Subjects (SOS) Study

A prospective, controlled intervention trial started in 1987.

Examines the effects of bariatric surgery compared to usual carePrimary endpoint:

Overall mortality

Secondary endpoints:DiabetesMIStroke

Main limitation: The non-randomized design

Surgery groupN=2010343 with diabetes

Control group N=2037260 with diabetes

Banding VBG GBP Usual care

SOS - A prospective, controlled intervention study

Inclusion criteria:37-60 years oldBMI men>34, women>38

Follow up:Up to 32 years, median over 20 years

Wei

ght c

hang

e, %

No. ExaminedControlBandingVBGGBP

2037376

1369265

1490333

1086209

1267284

1007180

55615048937

176508213

Follow-up time, years1242284987184

-35

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Control

Banding

VBG

GBP

Long term effects on body weightPercent weight change (95% CI)

From Sjöström, Peltonen, …….Carlsson. JAMA 2012

Diabetes was defined by:

Fasting blood glucose: ≥ 6.1 mmol/L (corresponding to fasting plasma glucose ≥ 7.0 mmol/L or ≥126 mg/dL)

and/or

Glucose lowering medication

Prediabetes was defined by:

Fasting blood glucose: 5.0–6.0 mmol/L (corresponding to fasting plasma glucose 5.6-6.9 mmol/L)

Diabetes and prediabetes in the SOS study

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2-year 10-year 15-yearFollow-up time

Control groupSurgery group

Diabetes remission inSOS patients with diabetes at baseline

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

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2-year 10-year 15-yearFollow-up time

Control groupSurgery group

Diabetes remission inSOS patients with diabetes at baseline

72%

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

Similar to observations in RTCs

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2-year 10-year 15-yearFollow-up time

Control groupSurgery group

72%

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

30%

Diabetes remission inSOS patients with diabetes at baseline

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2-year 10-year 15-yearFollow-up time

Control groupSurgery group

72%

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

30%

Diabetes remission inSOS patients with diabetes at baseline

Which patients stay in remission?

There were no baseline risk factor-treatment interactions(eg. BMI did not influence the results)

Type 2 diabetes is a progressive disease

Beta cells gradually lose the ability to produce insulin

Treatment benefit (remission) may depend on beta cell function

Importance of diabetes duration?

Which subgroups of patients obtain long-term diabetes remission?

Diabetes remission after bariatric surgery stratified by diabetes duration at baseline

Early treatment is important for remission

Sjöström et al, JAMA 2014

11800 patients with diabetes at baseline

The effect of diabetes duration in SOReg(Scandinavian Obesity Surgery Registry)

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Diabetes duration at the time of surgery

1-year Remission (%)in relation to diabetes

duration in SOReg

SOReg 2019

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1 år2 år5 år

1, 2 and 5-year Remission (%)in relation to diabetes

duration in SOReg

SOReg 2019Diabetes duration at the time of surgery

How early should we treat?

Many patients with obesity will develop diabetes.

Should we try to prevent this by bariatric surgery?

In which patients?

Both SOS and SOReg show that early treatment is important for remission

HR=0.22 (0.18-0.27), p<0.001Adj HR=0.17, p<0.001

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0 2 10 15Follow-up time, years

1658 1561 1225 576Surgery1771 1513 1076 404Control

Number at risk:

Control (392 events)Surgery (110 events)

Bariatric surgery strongly prevents diabetes

Around 80% risk reduction

Carlsson et al, N Engl J Med, Aug 23, 2012

NNT=4.6

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140

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(95%

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Control groupSurgery group

Baseline values, deciles

InteractionP=0.55

BMI

Effects of bariatric surgery on diabetes incidence in sub-groups defined by baseline BMI

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(95%

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Control groupSurgery group

Blood glucose, mg/dl Serum insulin, mU/L

Baseline values, deciles

InteractionP=0.007

InteractionP=0.007

InteractionP=0.55

BMI

Effects of bariatric surgery on diabetes incidence in sub-groups defined by baseline BMI, insulin or glucose

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Control groupSurgery group

Blood glucose, mg/dl Serum insulin, mU/L

Baseline values, deciles

InteractionP=0.007

InteractionP=0.007

InteractionP=0.55

BMI

Effects of bariatric surgery on diabetes incidence in sub-groups defined by baseline BMI, insulin or glucose

prediabetes

HR=0.26 (0.20-0.34), p<0.001

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Kapl

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Follow-up time, years

Control (237 events)Surgery (69 events)

Euglycemia

HR=0.17 (0.12-0.22), p<0.001

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Follow-up time, years

Control (155 events)Surgery (41 events)

Prediabetes

Diabetes prevention in patients euglycemia orprediabetes

NNT=7.0 NNT=1.3

Data from Carlsson et al, N Engl J Med, Aug 23, 2012

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

Retinopathy, nephropathy and neuropathy

56% risk reduction in patients with T2D

Bariatric surgery and prevention of microvascular complications in patients with T2D

Log-rank test P=0.001HR=0.55 (95% CI: 0.38-0.79)

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0 2 4 6 8 10 12 14 16Follow-up time, years

159 153 147 138 132 124 118 104 80Surgery87 81 81 76 69 62 51 38 25Control

Number at risk

Control (51 events)

Surgery (66 events)

Duration <1 yr

Log-rank test P=0.006HR=0.61 (95% CI: 0.42-0.87)

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Kapl

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0 2 4 6 8 10 12 14 16Follow-up time, years

93 90 86 83 74 66 56 36 23Surgery89 83 76 68 57 50 39 21 15Control

Number at risk

Control (65 events)

Surgery (54 events)

Duration 1-3 yrs

Log-rank test P=0.156HR=0.79 (95% CI: 0.56-1.09)

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Kapl

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0 2 4 6 8 10 12 14 16Follow-up time, years

91 84 75 63 49 40 33 23 13Surgery84 71 60 52 42 33 24 15 8Control

Number at risk

Control (69 events)

Surgery (72 events)

Duration ≥4 yrs

Early treatment is important for prevention of complications in T2D

45% risk reduction 39% risk reduction NS

Sjöström, Peltonen, …..Carlsson. JAMA, June 11, 2014

Obesity –> prediabetes –> T2D –> complications

Prevention Remission

How does timing of bariatric surgery affectprevention of microvascular complications?

At which stage is treatment benefit greatest?

What is the long-term effect of bariatric surgery on microvascularcomplications in patients with different baseline glucose status?

SOS study – baseline:Euglycemia: n=2838Prediabetes: n=591Screen detected T2D: n=246Established T2D: n=357

How early should we treat to prevent microvascular complications?

HR=0.63 (0.48-0.81)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Effect of bariatric surgery on microvascular events in SOS patients stratified by baseline glucose status (Retinopathy, nephropathy, neuropathy)

From Carlsson et al, Lancet D&E 2017

HR=0.63 (0.48-0.81)

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Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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0.90

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Effect of bariatric surgery on microvascular events in SOS patients stratified by baseline glucose status

46%risk reduction

From Carlsson et al, Lancet D&E 2017

HR=0.63 (0.48-0.81)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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0.80

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Effect of bariatric surgery on microvascular events in SOS patients stratified by baseline glucose status

46%risk reduction

61%risk reduction

From Carlsson et al, Lancet D&E 2017

HR=0.63 (0.48-0.81)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Effect of bariatric surgery on microvascular events in SOS patients stratified by baseline glucose status

82%risk reduction

46%risk reduction

61%risk reduction

From Carlsson et al, Lancet D&E 2017

HR=0.63 (0.48-0.81)

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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0.90

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0.70

0.80

0.90

Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Effect of bariatric surgery on microvascular events in SOS patients stratified by baseline glucose status

82%risk reduction

From Carlsson et al, Lancet D&E 2017

HR=0.18 (0.11-0.30)

0.00

0.10

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

Why are microvascular complications reduced by bariatric surgery in patients that have baseline prediabetes?

82%risk reduction

From Carlsson et al, Lancet D&E 2017

HR=0.18 (0.11-0.30)

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0.10

0.20

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

Why are microvascular complications reduced by bariatric surgery in patients that have baseline prediabetes?

82%risk reduction

Bariatric surgery strongly prevents diabetes.

From Carlsson et al, Lancet D&E 2017

HR=0.18 (0.11-0.30)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

Why are microvascular complications reduced by bariatric surgery in patients that have baseline prediabetes?

82%risk reduction

Bariatric surgery strongly prevents diabetes.

Is it only because bariatric surgery prevents diabetes?

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

78% risk reduction in patients that remain non-diabetic during follow-up

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

78% risk reduction in patients that remain non-diabetic during follow-up

Differences in glucose levels between surgery and control patients?

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

78% risk reduction in patients that remain non-diabetic during follow-up

Differences in glucose levels between surgery and control patients?

Slightly elevated glucose over long time?

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

78% risk reduction in patients that remain non-diabetic during follow-up

Differences in glucose levels between surgery and control patients?

Slightly elevated glucose over long time?

Normalized glucose levels after bariatric surgery?

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L

Fasting blood glucose at 2-years:

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L

Fasting blood glucose at 2-years:

Slightly elevated (prediabetic) glucose levels are associated with microvascular disease.

From Carlsson et al, Lancet D&E 2017

Log-rank test, p<0.001HR=0.22 (0.11-0.44)

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0.45

Kapl

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0 5 10 15 20Follow-up time, years

ControlSurgery

Patients with baseline prediabetes but without diabetes during follow-up

Microvascular complications

(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L

Fasting blood glucose at 2-years:

Slightly elevated (prediabetic) glucose levels are associated with microvascular disease.

Prediabetes should be treated!

From Carlsson et al, Lancet D&E 2017

HR=0.63 (0.48-0.81)

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0 5 10 15 20Follow-up time, years

Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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Kapl

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0 5 10 15 20Follow-up time, years

Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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0 5 10 15 20Follow-up time, years

Control

Surgery

T2D

Interaction p < 0.001

Microvascular complications in patients with euglycemia compared to prediabetes

From Carlsson et al, Lancet D&E 2017

Higher risk and benefit in prediabetes

Microvascular complications in SOS patients with euglycemia

Low normal High normal

Microvascular complications in SOS patients with euglycemia

The relative risk reduction after bariatric surgery was similar across the normoglycemic range

Low normal High normal

Microvascular complications in SOS patients with euglycemia

The relative risk reduction after bariatric surgery was similar across the normoglycemic range

0.00

0.10

0.20

0.30

0.40

0.50

0 5 10 15 20

Follow-up time, years

PrediabetesLow normal High normal

Health-care costs over 15 years after bariatric surgery and usual care in subgroups with:

- euglycemia- prediabetes- diabetes

Results from real data, not based on modeling!

What is the effect of baseline glucose status on long-term health-care costs?

0

10 000

20 000

30 000

40 000

50 000

60 000

70 000

80 000

90 000

100 000

Surgery Control Surgery Control Surgery Control

Euglycemic Prediabetes Diabetes

15-Year Accumulated Costs ($)

Inpatient Care

Outpatient Care

Drugs

P=0.81 P=0.007 P<0.0001

Data from Keating, Neovius, Sjöholm, Peltonen, Narbro, Eriksson, Sjöström & Carlsson

Lancet Diabetes Endocrinol. 2015 Sep 16

Drug costs were lower after surgery compared to usual carein patients with prediabetes or diabetes

Euglycemia

Prediabetes

Diabetes

Control group

Surgery group

Cost savings explained by reduced costs of diabetes drugs

Euglycemia

Prediabetes

Diabetes

Control group

Surgery group

Cost savings explained by reduced costs of diabetes drugs

Importance of long follow-up – it takes many years to detect a difference

0

10 000

20 000

30 000

40 000

50 000

60 000

70 000

80 000

90 000

100 000

Surgery Control Surgery Control Surgery Control

Euglycemic Prediabetes Diabetes

15-Year Accumulated Costs ($)

Inpatient Care

Outpatient Care

Drugs

P=0.86 P=0.38 P=0.90

Outpatient costs were similar in surgery and control patients for the three glucose groups

Data from Keating, Neovius, Sjöholm, Peltonen, Narbro, Eriksson, Sjöström & Carlsson

Lancet Diabetes Endocrinol. 2015 Sep 16

Euglycemia

Prediabetes

Diabetes

15-year inpatient costs were higher in surgery patients

0

10 000

20 000

30 000

40 000

50 000

60 000

70 000

80 000

90 000

100 000

Surgery Control Surgery Control Surgery Control

Euglycemic Prediabetes Diabetes

Inpatient Care

Outpatient Care

Drugs

P<0.0001 P<0.0001 P=0.09

15-year total healthcare costs are similar for surgical and non-surgical treatment in patients with baseline diabetes

Data from Keating, Neovius, Sjöholm, Peltonen, Narbro, Eriksson, Sjöström & Carlsson

Lancet Diabetes Endocrinol. 2015 Sep 16

P=0.01

P=0.48

15-Year Total Healthcare Costs By Diabetes DurationAdj. Mean Difference between Surgery and Control groups

US Dollar

Longer diabetes duration:Higher costs in surgery group

Data from Keating et al,Lancet Diabetes Endocrinol. 2015 Sep 16

P=0.01

P=0.48

15-Year Total Healthcare Costs By Diabetes DurationAdj. Mean Difference between Surgery and Control groups

US Dollar

Newly diagnosed diabetes:No difference between surgery and control groups

Longer diabetes duration:Higher costs in surgery group

Data from Keating et al,Lancet Diabetes Endocrinol. 2015 Sep 16

P=0.01

P=0.48

15-Year Total Healthcare Costs By Diabetes DurationAdj. Mean Difference between Surgery and Control groups

US Dollar

Newly diagnosed diabetes:No difference between surgery and control groupsLonger remissionBetter prevention of complications

Longer diabetes duration:Higher costs in surgery group

Data from Keating et al,Lancet Diabetes Endocrinol. 2015 Sep 16