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

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

-30

-25

-20

-15

-10

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5

0 1 2 3 4 6 8 10 15 20

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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72%


Similar to observations in RTCs

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

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


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


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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Follow-up time, years


Euglycemia

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

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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


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


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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


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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


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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Control

Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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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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Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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Control

Surgery

T2D


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

46%risk reduction


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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Control

Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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Surgery

T2D



46%risk reduction

61%risk reduction


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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Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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ST2D

HR=0.54 (0.40-0.72)

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Surgery

T2D



82%risk reduction

46%risk reduction

61%risk reduction


HR=0.63 (0.48-0.81)

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Euglycemia

HR=0.18 (0.11-0.30)

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Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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HR=0.54 (0.40-0.72)

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Surgery

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82%risk reduction


HR=0.18 (0.11-0.30)

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Surgery

Prediabetes

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

82%risk reduction


HR=0.18 (0.11-0.30)

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Surgery

Prediabetes


82%risk reduction

Bariatric surgery strongly prevents diabetes.


HR=0.18 (0.11-0.30)

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Control

Surgery

Prediabetes


82%risk reduction

Bariatric surgery strongly prevents diabetes.

Is it only because bariatric surgery prevents diabetes?


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

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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


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

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ControlSurgery




Differences in glucose levels between surgery and control patients?


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

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ControlSurgery





Slightly elevated glucose over long time?


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

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ControlSurgery





Slightly elevated glucose over long time?

Normalized glucose levels after bariatric surgery?


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

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ControlSurgery



(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L

Fasting blood glucose at 2-years:


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

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ControlSurgery



(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L


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


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

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ControlSurgery



(p<0.001)

4.18±0.55 mmol/L

4.86±0.65 mmol/L


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

Prediabetes should be treated!


HR=0.63 (0.48-0.81)

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Surgery

Euglycemia

HR=0.18 (0.11-0.30)

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Surgery

Prediabetes

HR=0.39 (0.24-0.65)

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Control

Surgery

ST2D

HR=0.54 (0.40-0.72)

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Control

Surgery

T2D


Microvascular complications in patients with euglycemia compared to prediabetes


Higher risk and benefit in prediabetes

Microvascular complications in SOS patients with euglycemia

Low normal High normal


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

Low normal High normal


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

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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?

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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

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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



Euglycemia

Prediabetes

Diabetes

15-year inpatient costs were higher in surgery patients

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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



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


US Dollar

Newly diagnosed diabetes:No difference between surgery and control groups



P=0.01

P=0.48


US Dollar

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



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

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