Update in Diabetes Care Exercise and Bariatric Surgery · • Two large Swedish registries merged...

Update in Diabetes Care

Exercise and Bariatric Surgery

Ted Adams, PhD, MPH

Intermountain LiVe Well Center Salt Lake

October 6, 2017

“There is no drug in current or perspective use that holds as much promise for sustained

health as a lifetime program of physical activity.”

American Medical Association

Physical Activity/Exercise and Diabetes:A Position Statement of the American Diabetes Association

Benefits of exercise/physical activity in diabetic patients

• Improve blood glucose control in type 2 diabetes

• Reduced cardiovascular risk factors

• Contributes to weight loss

• Improves well-being

• May prevent or delay type 2 diabetes

• Improve cardiovascular fitness, muscle strength, insulin sensitivity, etc.

Diabetes Care 2016;39:2065-2079

Rx Exercise/physical activity should be tailored to meet specific needs of each individual patient

• Refer to Table 3, page 2070, for specific recommendations related to types, intensity, duration and progression of exercise prescription.

• Refer to Table 5, page 2073, for physical activity considerations. Precautions and recommended activities for exercising with health-related complications.

• Be mindful of pregnancy, hypo- and hyper-glycemia, medication effects and heat-related illness

Diabetes Care 2016;39:2065-2079

ADA – Abridged Standards of Care, 2017*

Rx Exercise/physical prescription -children and adolescents

*Clinical Diabetes published online 12/15/2016

Type 1, type 2 or prediabetes – 60 min/day of moderate or vigorous intensity activity, with vigorous, muscle strengthening and bone-strengthening activities included at least 3

days/week

ADA – Abridged Standards of Care, 2017*

Rx Exercise/physical prescription -most adults, Type 1 and 2

*Clinical Diabetes published online 12/15/2016

• Type 1 or type 2 –150 min or more of moderate-to-vigorous intensity activity per week (spread out over at least 3 days/wk, not missing more than 2 days in a row

• 2-3 sessions/wk or resistance exercise (not in a row)• Decrease time spent in sedentary behavior; interrupt

prolonged sitting every 30 min• Flexibility and balance training 2-3 times/wk for older

adults (yoga and tai chi - flexibility, strength, balance

Prospective and retrospective observational studies in bariatric surgery

• Can contribute (in a unique way) to the understanding of long-term outcomes of bariatric surgery.

• Electronic medical record

• Health plans claims data

• Combined health plans claims data

• RCTs in bariatric surgery have some limitations

• Difficult to recruit participants

• May be under-powered for adequate analyses

Reduction of Micro- and Macrovascular Complications (Johnson BJ et al.; 2013)

• Pre-bariatric surgical patients (BAR) with T2DM(n=2580); surgery, 1996-2009

• Moderate and obese non-bariatric surgical patients (No-BAR) with T2DM (n=13,371)

• Both groups without MI, angina, CHF, stroke, or advanced microvascular disease

• Study outcome: First major macrovascular or microvascular event BAR to No-BAR

Johnson BJ et al. J Am Coll Surg 2013;216:545-58

Disease HR

Macrovascular 0.39; 95% CI, 0.29-0.51

Microvacular 0.22; 95% CI, 0.09-0.49

Multisite Study of Long-term Remission and Relapse of T2DM (Arterburn; 2013)

Pre-bariatric surgical patients with T2DM (n=4,434); 1995-2008

• Initial T2DM remission within 5 years post-surgery:

68.2% (95% CI, 66-70%)

• Remitters who redeveloped T2DM remission within 5 years

• 35.1% (95% CI, 32-38%)

Arterburn DE et al. Obes Surg 2013;23(1):93

• Two large Swedish registries merged – National Diabetes

Registry & Scandinavian Obesity Surgery Registry

• 6132 RYGB patients and 6132 non-surgery control patients –

all patients with T2DM

• Matched on sex, age, BMI, calendar time

• 3.5 years follow-up

Eliasson, B, Lancet Diabetes Endocrinol, 2015;3:847

Retrospective – Pre-surgery T2DM andCVD Incidence and Mortality (Eliasson; 2015)

EventsRYGB

Patients (N)

Non-operated

(N)HR (95% CI)

All-cause mortality 82 288 0.42 (0.3-0.6)

CVD-caused mortality

13 67 0.41 (0.2-0.9)

Fatal or non-fatal MI 24 67 0.51 (0.3-0.91)

Eliasson cont. – all patients with T2DM (n=6132; each group, )

Eliasson, B, Lancet Diabetes Endocrinol, 2015;3:847

PROMISE study– NIH Funded (Arterburn; 2016)

Joint collaboration between 4 U.S. health care systems:

• Kaiser Permanente Northern California (KPNC)

• Kaiser Permanente Southern California (KPSC)

• HealthPartners Research Foundation in Minnesota (HPRF)

• Group Health Cooperative (GHC)

Approximately 10,000 bariatric surgical patients who were

diabetic prior to surgery (surgery – 2001 through 2011; 40%

racial/ethnic minority)

PROMISE study (continued)

First manuscript – Long-term microvascular disease (first occurrence ofretinopathy, neuropathy, and/or nephropathy)

• Those who remitted T2DM = 29% lower risk of microvascular

disease compared to never-remitted (HR 0.71 [95% CI 0.60, 0.85])

• For those who remitted T2DM and later relapsed, the longer the

remission time inversely related to risk for incident microvascular

disease

• Every additional year of remittance = reduced risk of 19% (HR 0.81

[95% CI 0.67, 0.99])

Coleman KJ et al. Diab Care 2016 (online pub)

Geisinger Obesity Institute – CVD Risk Factors and CHF (Benotti; 2017)

• RYGB group and matched controls, n=1724

• Matched on: age, BMI, sex, Framingham Risk Score, smoking

Hx, HTN meds, T2DM and date of surgery

• Primary end points: MI, stroke and CHF

• Secondary end points: CVD risk factors (risk score, lipids,

SBP, and T2DM)

• Follow-up: 12 years post-surgery (mean = 6.3 years)

Benotti PN et al. J Am Heart Assoc 2017;6:e005126

Geisinger Obesity Institute – results

• Reduction in major composite CV events (63 in RYGB group

and 110 in control group) – HR 0.58 (95% CI: 0.42, 0.82)

• Reduction in CHF in RYGB compared to controls (p=0.0077)

but not significantly different for MI and stroke alone

• Improvements in CV risk factors (p<0.0001)

Benotti PN et al. J Am Heart Assoc 2017;6:e005126

Groups MI (N) Stroke (N) CHF

RYGB 12 31 24

Matched Controls 17 49 55

• French health care system database, SNIRAM, linked to

French medical discharge database, PMSI

• 1633 bariatric surgery patients and 1633 matched controls

• Follow-up of 6 years; greatest benefit in RYGB subgroup

Thereaux, J et al, data presented at IFSO London, 2017.

Thereaux J et al. – Retrospective Nationwide Matched Cohort Study

EventsBariatric Surgery

PatientsNon-operated (N)

Remitted T2DM 50% 9%

T2DM Incidence 1% 12%

SOS Long-term Micro- and Macro-vascular Complications (Sjöström L et al.)

Macrovascular complications of BAR vs. No-BAR

• BAR – 20.6 per 1000 person–years

• No-BAR – 41.8 per 1000 person-years

• HR 0.44; 95% CI, 0.34-0.5; p<0.001

Microvascular complications of BAR vs. No-BAR

• BAR – 31.7 per 1000 person–years

• No-BAR – 44.2 per 1000 person-years

• HR 0.68; 95% CI, 0.54-0.85; p=0.001

Sjöström L et al. JAMA 2014;311:2297

One RCT - Micorvascular & Macrovascular Outcomes - STAMPEDE (Schauer, P. et al.)

Reduction in urinary albumin-to-creatinine ratio (UACR) of SURG vs. No-SURG (p<0.04) for both GBP and sleeve groups

Patients with baseline albuminuria who returned to normal values:

• 62% (8 of 13; p=0.04 within group comparison)

• 80% (8 of 10; p=0.11 within group comparison)

• 25% (1 of 4; p=1.00 within group comparison)

Schauer, P. et al. NEJM 2014;370:2002

Utah Study - Hypothesis

Does Roux-en-Y gastric bypass (RYGB) surgery

result in improved morbidity when severely obese

non-surgical groups (population-based and

denied-surgery) are compared to RYGB patients?

Note: Gastric banding was not approved in USat time of study initiation (2001).

Health plan approves RYGB or patient provides self-pay and

RYGB surgery performed

Recruitment Scheme:RYGB Group and Non-surgery Group 1

Patients come to surgeon’s clinic to learn about RYGB and get health insurance advice. Patients informed of study.

Patient agrees to participate

Patient undergoes baseline testing

Patient assigned toRYGB Group

Patient assigned toNon-surgical group 1

Health plan denies coverage of RYGB or patient chooses not to

have RYGB performed

Recruitment Scheme:Non-surgery Group 2

• Severely obese participants not seeking bariatric surgery.

• Randomly selected from the Utah Health Family Tree

program database:

• 150,000+ families (>1 million family members)

• Health data, including reported weight status.

Recruitment Hypothesis

• Denied surgery patients (Non-surgical Group 1) represent

characteristics associated with seeking surgery (potentially

self-selected for significant comorbidities and other

conditions).

• Population-based severely obese participants (Non-surgical

Group 2) represent characteristics associated with severely

obese subjects in the general population.

Long-term Prospective Utah Study(NIH-funded 2001-2015)

387

388

Exam 3

410

400

Exam 2Exam 1

2 Years 6 YearsBaseline

417

No

RYGB

418

RYGBSurgical

Center

12 Years

315319321

Utah

Health

Family

Tree

Program301

388

364

Exam 4

Adams et al. Obesity 2010;18:121-30

RYGB Surgery

Non-Surgery 1

Non-Surgery 2

Adams et al. JAMA 2012;308:1122-31

12-year Results – Follow-up

End Point RYGB Surgery Group

(minus deaths)

Non-surgery Group 1

(minus deaths)

Non-surgery Group 2

(minus deaths)

Potential Participation, n 392 378 303

Any data source, n (%) 388 (98.7%) 364 (96.3%) 301 (99.3%)

Minimum of Weight, SBP, and either glucose or

HbA1c, n (%)353 (90.1%) 342 (90.5%) 285 (94.1%)

Later had bariatric surgery, n (%)

--- 147 (35%) 39 (12%)

Adams, T. et al. NEJM 2017;377:1143-55

12-year Results – Mortality

End Point

RYGB Surgery Group

(minus deaths)

Non-surgery Group 1

(minus deaths)

Non-surgery Group 2

(minus deaths)

All-cause, n (%) 26 (6.2%) 39 (9.4%) 18 (5.6%)

CVD, (n) (%) 3 17 8

Cancer, n (%) 4 5 7

Suicide, n (%) 5 (1.2%) 2 (0.5%)* 0

Poisoning, n (%) 4 (1.0%) 2 (0.5%) 0

* = Death subsequent to bariatric surgery

Adams, T. et al. NEJM 2017;377:1143-55

-50

-40

-30

-20

-10

0

10

BL 2 Years 6 Years 12 Years

% C

hange

Control 2

Control 1

Surgery

*

* *

% Change in Baseline Body Weight (mean adjusted)

* = Surgery group differs significantly from non-surgery groups; p<0.001 Adams, T. et al. NEJM 2017;377:1143-55

# of participants Baseline 2 Years 6 Years 12 Years

RYGB patients 418 409 379 387

Deaths --- 3 9 14

Total 418 412 388 401

% Change in Baseline Body Weight RYGB Group

-70

-60

-50

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-30

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-10

0

10

20

2001 2004 2006 2009 2012 2014 2017

Perc

ent

weig

ht

change f

rom

baseline Baseline

2-yr

6-yr

12-yr

% weight lost

% Change in Baseline Body WeightNon-Surgery Group 1

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

2001 2004 2006 2009 2012 2014 2017

Perc

ent

weig

ht

change f

rom

baseline

Baseline

2-yr

6-yr

12-yr

2-yr surgery

6-yr surgery

12-yr surgery

Non-surgical controls

All controls including surgeries

# of participants Baseline 2 Years 6 Years 12 Years

Non-surgery group 1 417 373 294 217

Had surgery later --- 28 89 146

Deaths --- 3 11 25

Total 417 404 394 388

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

70

2001 2004 2006 2009 2012 2014 2017

Perc

ent

weig

ht

change f

rom

baseline

Baseline

2-yr

6-yr

12-yr

2-yr surgery

6-yr surgery

12-yr surgery

Population controls

All controls including surgeries

# of participants Baseline 2 Years 6 Years 12 Years

Non-surgery group 2 321 312 294 262

Had surgery later --- 8 19 39

Deaths --- --- 3 15

Total 321 320 316 316

% Change in Baseline Body WeightNon-Surgery Group 2

Weight Loss Maintenance at 12 Years: RYGB Group

• 360 of 387 RYGB patients (93%) maintained at least a 10% weight loss from baseline to year 12

• 271 (70%) maintained at least 20% weight loss

• 155 (40%) maintained at least 30% weight loss

• Only 4 of 387 (1%) had regained all postsurgical

weight loss

Adams, T. et al. NEJM 2017;377:1143-55

Diabetes remission after RYGB

Group 2 years 6 years 12 years

Surgery, % 74% 62% 51%

Surgery, n 66/88 54/87 43/84

Adams, T. et al. NEJM 2017;377:1143-55

Diabetes and Hypertension:12-year Remission

End

Point

Surgery

%

NS 1, % NS 2, % Adj. OR

S vs NS 1

Adj. OR

S vs NS 2

T2D 51% 10% 5%8.9***

(2.0, 40.0)

14.8***(2.9, 75.5)

HTN 36% 10% 14%5.1***

(1.7, 15.6)

2.4(0.9, 5.9)

*** = P<0.001

Adams, T. et al. NEJM 2017;377:1143-55

Diabetes and Hypertension: 12-year Incidence

End

Point

Surgery

%

NS 1, % NS 2, % Adj. OR

S vs NS 1

Adj. OR

S vs NS 2

T2D 3% 26% 26%0.08***

(0.03, 0.24)

0.09***(0.03, 0.24)

HTN 16% 41% 47%0.23***

(0.11, 0.49)

0.09***(0.11, 0.51)

*** = P<0.001

Adams, T. et al. NEJM 2017;377:1143-55

30

35

40

45

50

55

60

65

BL 2 Years 6 Years 12 Years

mg

/dL

Surgery Group Non-S Group 1 Non-S Group 2

**

*

Unadjusted Mean HDL-Cholesterol

*Surgery group mean (adjusted for medication use) differs significantly from non-surgery groups; p<0.05

Adams et al. JAMA 2012;308:1122-31Adams et al. Obesity 2010;18:121-30Adams, et al. NEJM 2017;377:1143-55

0

50

100

150

200

250

BL 2

Years

6

Years

12

Years

gra

ms

Surgery Group Non-S Group 1 Non-S Group 2

** *

Left Ventricular Mass

Adams et al. JAMA 2012;308:1122-31Adams et al. Obesity 2010;18:121-30Adams, et al. NEJM 2017;377:1143-55

Conclusions

• Long-term durability of weight loss after RYGB with minimal

weight increase between the 6- and 12-year follow-up

• Very minimal incidence of T2DM

• Remission rate 51% at the 12-year follow-up

• Marked improvement in systolic hypertension and lipid levels

Acknowledgement: Funding from NIH-NIDDK

Thank You

“There is no drug in current or perspective use that holds as much promise for sustained

health as a lifetime program of physical

activity.”

Journal of the American Medical Association

Benefits of Physical Activity

Lower death rates

Prevents or reduces risk of:

• High blood pressure

• Osteoporosis

• Overweight and obesity

• Depression and anxiety

• Diabetes

• Some cancers (i.e. colon)

Benefits of Physical Activity

Improves structure and function of ligaments, tendons and joints

Improves:

• Muscular strength

• Sleep patterns

• Health-related quality of life

• Independent living with increasing age

Rx Structured Exercise

Program

Frequency: 3-5 days/week

Intensity: 55/65% - 90% max heart rate

Rx Structured Exercise

Program continued

Duration: 20-60 min (continuous or intermittent - minimum 10 min. bouts accumulated over the day)

Mode: Large muscle groups, continuous, aerobic in nature

Modes for Structured Exercise

Walking-hiking

Running-jogging

Cycling-bicycling

Aerobic dance

Stair climbing

Swimming

Endurance games

Resistance training: One set, 8-10 exercises, 8-12 reps, 2-3 days/wk

Rx Structured Exercise

Program continued

Examples of Using YourOwn Weight

Flexibility training: 2-3

days/wk of stretching

major muscle groups

Rx Structured Exercise

Program continued

Flexibility Exercises

Rx Lifestyle Physical Activity

Accumulate 30 minutes or more of moderate-intensity physical activity on most, preferably all days of the week.

Resistance training 2 times per week

Examples: Moderate Intensity Activities

Walking

Yard Work

Stair Climbing

Housework

Dancing

Resting Metabolic Rate (RMR)

• Indirect calorimetry using a Parvomedics TrueOne 2400 metabolic cart.

• Measurements taken in the morning after a 12-hour fast, minimal exercise in prior 24 hours, and participants having rested in a supine position for at least 30 minutes.

• 24-hour estimates based on at least 10 minutes of stable resting values.

• 986 participants had at least one assessment

Mixed model regression was used to determine group-wise differences at each time point.

1500

1600

1700

1800

1900

2000

2100

2200

2300

2400

2500

BL 2 Years 6 Years 12 Years

kcals

/day

Non-Surgery 2

Non-Surgery 1

Surgery

Resting Metabolic Rate (RMR)

†‡ †‡

‡

*

*

**

*

*/*/* Within-group change from previous assessment is significant (p<0.05)† Surgery value differs significantly from Non-Surgery 1 group (p<0.05)‡ Surgery value differs significantly from Non-Surgery 2 group (p<0.05)

†‡

*

• RMR has an expected drop with weight loss in Surgery group

• Long-term rate of RMR decrease mirrors age-related drop in controls

12

13

14

15

16

17

18

19

20

21

22

BL 2 Years 6 Years 12 Years

kcals

/day

Non-Surgery 2

Non-Surgery 1

Surgery

Resting Metabolic Rate (RMR) per kg body weight

†‡

†‡

‡

*/*/* Within-group change from previous assessment is significant (p<0.05)† Surgery value differs significantly from Non-Surgery 1 group (p<0.05)‡ Surgery value differs significantly from Non-Surgery 2 group (p<0.05)

†‡

*

*

*

**

**

• Per kilogram RMR remains improved long-term, perhaps explaining maintenance of post-op weight loss

• Difference begins to wane by 12 years

RYGB: influence of Fat and FFM on RMR

0

500

1000

1500

2000

2500

0

20

40

60

80

100

120

140

160

BL 2 yrs 6 yrs 12 yrs

kilo

gra

ms

FFM

FM

Weight

RMR

*

*

* **

*/*/*/* Change is significant (p<0.05) compared with previous assessment

*

**

*

**

• RMR does not decrease as much as expected with weight loss

• FFM constitutes 1/3rd of weight loss, but is only 11% of regain

RYGB: influence of Fat and FFM on RMR/kg

0

5

10

15

20

0

20

40

60

80

100

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BL 2 yrs 6 yrs 12 yrs

Kcals

/kg/d

ay

kilo

gra

ms

FFM

FM

Weight

RMR/kg

**

* **

*

** *

**

*

• RMR/kg changes reflect increased FFM relative to FM

*/*/*/* Change is significant (p<0.05) compared with previous assessment

Cardiorespiratory fitness: time on treadmill

Time Test type RYGB

(seconds)

NS 1

(seconds)

NS 2

(seconds)

BaselineSubmax

(80%)602±13 593±14 582±13

2 years Maximal 873±13 623±16*** 586±14***

6 years Maximal 828±14 641±17*** 679±13***

12 yearsSubmax

(80%)643±14 598±16* 556±17***

• Graded exercise test with 12-lead ECG

• Submaximal tests at baseline and 12 years (maximal tests at 2 and 6 years)

• Means are seconds to test completion

• After surgical weight loss, RYGB patients are able to last significantly longer on the treadmill 10-12 years after surgery

• The effect is lost when controlling for weight

* = (p<0.05)*** = (p<0.0001)