Leveraging Weight Loss in the Treatment of Type 2 Diabetes

Part 1 of 4

Overview• Overweight/obesity health risks associated with type 2

diabetes• American Diabetes Association (ADA) guidelines for

medical nutrition therapy (MNT) and lifestyle changes• Glycemic benefits and additional advantages of weight loss

in type 2 diabetes• Application to clinical practice

Bo

dy

We

igh

t (l

b)

200

220

240

260

280

300

320

Adapted from Kendall DM, et al. © 2004 International Diabetes Center, Minneapolis, MN. All rights reserved.

Years

DiabetesDiagnosis

Onset

Prediabetes (IFG, IGT)Metabolic Syndrome

Fasting Glucose

Postmeal Glucose

Glu

co

se

(m

g/d

L)

50

100

150

200

250

300

350

Obesity, Inactivity,Genetics

Re

lati

ve

Fu

nc

tio

n

-10 -5 0 5 10 15 20 25 30

Insulin Resistance

Insulin Response

0

50

100

150

200

250

-15

Progressive -Cell Defect (glucose specific)

Amylin Response

Oral Agents/Incretin Enhancers

Basal Insulin

Basal/Bolus Insulin

Amylin Replacement

Natural History of Type 2 Diabetes and Obesity

Prevalence of Overweight and Obesity Among Adults Diagnosed With Diabetes

BMI = body mass index.

Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2004;53:1066-1068.www.cdc.gov/mmwr/preview/mmwrhtml/mm5345a2.htm. Accessed April 9,2008.

20-64 ≥650

20

40

60

80

100

Age (years)

%

Obese (BMI ≥30)

Overweight or Obese (BMI ≥25)

Health Risks of Obesity • Increased morbidity

– Hypertension– Dyslipidemia – Coronary heart disease– Type 2 diabetes– Stroke– Cancer (endometrial, breast, colon)– Impairments in health-related quality of life and

psychosocial well-being– Sleep apnea– Osteoarthritis

• Increased mortality

NIH-NHLBI. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. 1998.

Excess Weight in Individuals With Type 2 Diabetes Increases Mortality Risk

Comorbidities of Obesity

TC = total cholesterol; Ref category = normal weight without the risk factor.

Wei M, et al. JAMA. 1999;282:1547-1553.

Relative Risk of All-Cause Death by BMI Categories for Selected Mortality Predictors

Ref Category Normal Overweight Obese

Rel

ativ

e R

isk

Ad

just

ed

for

Ag

e an

d E

xam

Yea

r

0

0.5

1

1.5

2

2.5

3

3.5

TC >239 Diabetes Hypertension Smoker

Additional Problems Associated With Obesity in Individuals With Type 2 Diabetes

• Exacerbation of metabolic risk factors– Hyperglycemia– Dyslipidemia– Increased thrombogenic risk (eg, increased PAI-1)

• Increased insulin resistance and glucose intolerance• Increased risk of hypertension and cardiovascular disease• Increased mortality

– Mortality ratio for individuals with diabetes whose body weights are 20% to 30% above ideal is 2.5 to 3.3 times higher than those of normal body weight

PAI-1 = Plasminogen activator inhibitor-1.

Maggio CA, et al. Diabetes Care. 1997;20:1744-1766.

Additional Problems Associated With Obesity in Individuals With Type 2 Diabetes

• Exacerbation of metabolic risk factors– Hyperglycemia– Dyslipidemia– Increased thrombogenic risk (eg, increased PAI-1)

• Increased insulin resistance and glucose intolerance• Increased risk of hypertension and cardiovascular disease• Increased mortality

– Mortality ratio for individuals with diabetes whose body weights are 20% to 30% above ideal is 2.5 to 3.3 times higher than those of normal body weight

PAI-1 = Plasminogen activator inhibitor-1.

Maggio CA, et al. Diabetes Care. 1997;20:1744-1766.

Standards of Medical Care in Type 2 Diabetes: 2008 ADA Glycemic Goals

• A1C <7.0%– Preprandial glucose 70-130 mg/dL– Postprandial glucose (PPG) <180 mg/dL

• At diagnosis: Metformin (MET) and lifestylechanges (MNT)– Add therapy to reach A1C of <7%– Add therapy to maintain an A1C of <7%

• Target PPG if A1C goals are unmet, despite reaching preprandial glucose

American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S54.

Standards of Medical Care in Type 2 Diabetes: 2008 ADA Weight Recommendations

• Weight loss is an important therapeutic objective1

– 85% of individuals with type 2 diabetes are obese/overweight2 • Physical activity and behavior modification are important1

• Moderate weight loss (5% in short-term studies)1

– Decreased insulin resistance– Improved measures of glycemia and lipemia– Reduced blood pressure

• “The importance of controlling body weight in reducing risks related to diabetes is of great importance…” but sustaining weight loss is difficult1

1. American Diabetes Association. Diabetes Care. 2008;31(suppl 1):S12-S78.2. www.cdc.gov/mmwr/preview/mmwrhtml/mm5345a2.htm. Accessed April 9,2008.

Modest Weight Loss Can Drastically Reduce Abdominal Visceral Fat

Before Weight Loss

(95 kg, BMI 32)After 10% Weight Loss

(85 kg, BMI 29)

Després J-P. Baillière’s Clin Endocrinol Metab. 1994;8:629-660.

Weight Loss in Type 2 Diabetes:Study Objective and Design

• Objective: Determine if modest weight loss would provide a long-term benefit

Weight Control Program• Group treatment• Individualized treatment goals to produce

a 1-kg/wk weight loss• Calorie/food restriction with focus on reduced

fat intake• Gradual increase of exercise goals with final

goal of 3.2 km/d, 5 days per week• Behavior-modification strategies

1-Year Follow-up Physical

Wing RR, et al. Arch Intern Med. 1987;147:1749-1753.

N=114

Type 2 diabetes treated with insulin, orals, diet only, or insulin plus oral

medications

Weight Loss in T2DM Dramatically Improves Glycemia and Metabolic Risk Factors

Δ Body Weight (%)

Δ A1C

Δ Body Weight (kg)

-2 to

-4.9

-5 to

-9.9

0

-0.4

0.4

0.8

00

to -1

.9

> -1

0

-0.8

-1.2

-1.6

-20

-40

0

Δ Triglycerides (mg/dL)

0

0 to

-2.3

-2.4

to -6

.8-6

.9 t

o -1

3.6

> -1

3.6

-60

-80

-100

Δ HDL-C (mg/dL)

8

6

10

12

4

2

0

00

to -2

.3-2

.4 to

-6.8

-6.9

to

-13.

6>

-13.

6

Δ Body Weight (kg)

Wing RR, et al. Arch Intern Med. 1987;147:1749-1753.

Hamdy O, et al. Diabetes Care. 2003;26:2119-2125.Monzillo LU. Obes Res. 2003;11:1048-1054.

Ch

ang

e F

rom

Bas

elin

e (%

) IL-6 TNF- hCRP PAI-1 Leptin

P<.05 NS NS P<.001 P<.01 NS

Adiponectin

-16.3 -17.4-18.7

-25.5

-15.7

4.3

-30

-25

-20

-15

-10

-5

0

5

Benefits of Weight Reduction on Cytokines in Type 2 Diabetes and Prediabetes