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

Natural History of Type 2 Diabetes and Obesity

320 Body Weight (lb) 300 280 260 240 220 200 350 Glucose (mg/dL) 300 250 200 150 100 50 Relative Function 250 200 150 100 50 0

Obesity, Inactivity, Genetics

Oral Agents/Incretin Enhancers Postmeal Glucose Basal Insulin Fasting Glucose Basal/Bolus Insulin Amylin Replacement

Insulin Resistance
Progressive -Cell Defect (glucose specific)
Prediabetes (IFG, IGT) Metabolic Syndrome
Diabetes Diagnosis

Insulin Response 15 20
Amylin Response

-15

-10

-5

0
Onset

10 Years

25

30

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

Prevalence of Overweight and Obesity Among Adults Diagnosed With Diabetes

100 Overweight or Obese (BMI 25) Obese (BMI 30) 80

60 % 40 20 0

20-64
BMI = body mass index.

65 Age (years)

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.

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

Relative Risk of All-Cause Death by BMI Categories for Selected Mortality Predictors
3.5 Relative Risk Adjusted for Age and Exam Year 3 2.5 2 1.5 1 0.5 0 TC >239 Diabetes Hypertension Smoker

Comorbidities of Obesity

Ref Category

Normal

Overweight

Obese

TC = total cholesterol; Ref category = normal weight without the risk factor. Wei M, et al. JAMA. 1999;282:1547-1553.

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 lifestyle changes (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)

Desprs J-P. Baillires 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
N=114

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

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.

Weight Loss in T2DM Dramatically Improves Glycemia and Metabolic Risk Factors
A1C
0.8 0 0.4 10

Triglycerides (mg/dL)
12

HDL-C (mg/dL)

-20
0 -40 -0.4 -60 -0.8 -80 -1.2 -100 -1.6 0 2 4 6 8

Body Weight (%)

Body Weight (kg)

Body Weight (kg)

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

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

P<.05
5

NS

NS

P<.001

P<.01

NS
4.3

Change From Baseline (%)

IL-6

TNF-a

hCRP

PAI-1

Leptin Adiponectin

0 -5 -10

-15
-20 -25 -30
-25.5 -16.3 -17.4

-15.7
-18.7

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