Welcome and Introduction

This presentation will:

• Define obesity, prediabetes, and diabetes

• Discuss the diagnoses and management of obesity, prediabetes, and diabetes

• Explain the early risk factors for diabetes and the rationale for aggressive treatment to delay or prevent diabetes onset

Defining Obesity – A Disease• Body Mass Index (BMI)

– Evaluates weight relative to height (kg/m2)

– Correlates highly with body fat, morbidity, and mortality

• Categories:

Handelsman Y et al. Endocr Pract. 2016;22(Suppl 1):34.

Table 6. Classification of Ov erweight and Obesity by BMI and Waist Circumference (31[EL 4; NE])

Classification

BMI Waist

BMI (kg/m2)Comorbidity

Risk

Waist Circumference andComorbidity Risk

Men < 40 in (102cm)Women < 35 in (88cm)

Men > 40 in (102cm)Women > 35 in (88cm)

Underweight <18.5 Low but other problems

Normal weight 18.5-24.9 Average

Overweight 25-29.9 Increased Increased High

Obese class I 30-34.9 Moderate High Very high

Obese class II 35-39.9 Severe Very high Very high

Obese class III >40 Very severe Extremely high Extremely high

Abbreviation s : BMI = body ma ss inde x; in = inches

BMI = body mass index.

Overweight and Obesity Prevalence Increasing Among U.S. Adults

Flegal KM et al. JAMA 2002;288:1723-27; Hedley AA et al. JAMA 2004;291:2847-50; Ogden CL et al. JAMA2006;295:1549-55; Flegal KM et al. JAMA 2012;307(5):491-7.

0.

17.5

35.

52.5

70.

87.5

1960-62 1971-74 1976-80 1988-94 1999-2002 2003-2004 2009-2010

Pre

va

len

ce

(%

) .

NHANES Data Collection Period

Overweight Obesity

NHANES = National Health and Nutrition Examination Survey.

Age-adjusted Prevalence of Obesity and Diagnosed Diabetes Among US Adults

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0%–17.9% 18.0%–21.9% 22.0%–25.9% > 26.0%

No Data <4.5% 4.5%–5.9% 6.0%–7.4% 7.5%–8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

2013

2013

BMI = body mass index; CDC = U.S. Center for Disease Control and Prevention.

An Expensive Epidemic

• Currently, 69% of American adults are overweight and nearly 38% are obese

• Compared to non-obese individuals, obesity adds $3,559 per patient to total annual health care costs

– This includes $1,130 per patient to annual pharmacy costs

• As much as 27.5% of annual medical spending in the U.S. is obesity-related

• In the U.S., medical costs for obesity are at least $190.2 billion per year

– Some studies estimate current obesity-related costs as high as $315.8 billion

Garvey W et al. Endocrine Practice 2016;22 (Suppl 3):1-203; Cawley J et al. PharmacoEconomics 2015;33:707-722; 2014

AACE/ACE Consensus Conference on Obesity. Executive Summary.

Available at: http://mms.businesswire.com/media/20140325006164/en/408761/1/aace.pdf

Medical Complications of Obesity

Coronary heart disease

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Gall bladder disease

Gynecologic abnormalitiesabnormal mensesinfertilitypolycystic ovarian syndrome

Gout

Stroke

Diabetes

Osteoarthritis

Cancerbreast, uterus, cervixcolon, esophagus, pancreaskidney, prostate

Nonalcoholic fatty liver diseasesteatosissteatohepatitiscirrhosis

Hypertension

Dyslipidemia

Cataracts

Skin

Idiopathic intracranial hypertension

Severe pancreatitis

Phlebitisvenous stasis

Health Benefits of Modest Weight Loss

• Loss of 5% to 10% of body weight can result in:

– Decreased cardiovascular risk, blood glucose and insulin levels, blood pressure, LDL cholesterol and triglycerides, sleep apnea severity, and degenerative joint disease symptoms

– Increased HDL cholesterol

– Improvement in multiple cardiovascular risk factors, and other complications, including gynecologic conditions

Handelsman Y et al. Endocr Pract. 2016;22(Suppl 1):34.The Practical Guide to the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults;

HDL = high density lipoprotein; LDL = low density lipoprotein.

Relationship Between BMI and Risk of Type 2 Diabetes Mellitus

Chan J et al. Diabetes Care 1994;17:961.; Colditz G et al. Ann Intern Med 1995;122:481.

Age

-Ad

just

ed R

elat

ive

Ris

k

<23 24–24.9 25–26.9 27–28.9 33–34.9

0

25

50

75

100

1.0

2.9 4.3 5.08.1 15.8

27.6

40.3

54.0

93.2

<22 23–23.9 29–30.9 31–32.9 35+

1.0 1.52.2

4.4

6.711.6

21.3

42.1

1.0

Men

Women

BMI (kg/m2)

BMI = body mass index.

Adipose Tissue in Obesity

Lean

Gustafson: Arterioscler Thromb Vasc Biol, 27(11): 2276-2283, 2007

Obese

Prediabetes

Impaired Fasting Glucose (IFG):

FPG 100-125 mg/dL (5.6-6.9 mmol/l)

or

Impaired Glucose Tolerance (IGT):

2-h plasma glucose in the 75-g OGTT140-199 mg/dL (7.8-11.0 mmol/l)

or

A1C 5.7% to 6.4%

Handelsman Y et al. Endocrine Practice 2015;21 (Suppl 1)

A1C = glycated hemoglobin; FPG = fasting plasma glucose; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; OGTT = oral glucose tolerance test.

Overall incidence: 4% to 10%/year

American Diabetes Association. Diabetes Care. 2003;26:917-932.; Nathan D, et al. Diabetes Care. 2007;30(3):753-759.

Progression to Diabetes

• Over 3 to 5 years, 25% of patients with prediabetes will develop diabetes, while 50% will remain in the category of IFG or IGT; 25% will have normal glucose tolerance.

IFG = impaired fasting glucose; IGT = impaired glucose tolerance; UK = United Kingdom.

5% per year with metforminvs 10% per year by lifestyle intervention

58%

Diabetes Prevention Program: An Example of Effectiveness

Outcomes of Modest Weight Loss and Lifestyle Changes

DPP Research Group. N Engl J Med 2002;346:393-403.

Placebo

Metformin

Lifestyle

Effect of Treatment on Incidence of Diabetes

Placebo Metformin Lifestyle

Incidence of diabetes 11.0% 7.8% 4.8%

(% per year)

Reduction in incidence ---- 31% 58%

vs. placebo

Number needed to treat ---- 13.9 6.9

to prevent 1 case in 3 years

The DPP Research Group. NEJM 2002; 346:393-403

Diabetes

• Diabetes is defined as:

– Fasting blood glucose ≥ 126 mg/dL

– 2-hour postprandial glucose ≥ 200 mg/dL

– A1C ≥ 6.5%

Handelsman Y et al. Endocrine Practice 2015;21 (Suppl 1)

A1C = glycated hemoglobin.

Main Pathophysiological Defects in T2DM “The Ominous Octet”

Islet b-cell

Impaired

insulin secretion

Neurotransmitter

dysfunction

Decreased glucose

uptake

Islet a-cell

Increased

glucagon secretion

Increasedlipolysis

Increased glucose

reabsorption

Increased

hepatic

glucose

production

Decreasedincretin effect

Defronzo RA. Diabetes. 2009 Apr;58(4):773-95.

T2DM = type 2 diabetes mellitus.

LoweringA1C

Preventing Hypoglycemia

Glycemic Management of Type 2 Diabetes: Treatment Goals

Individualized Algorithm

A1C = glycated hemoglobin.

Approach To Management of Hyperglycemia

ADA. V. Diabetes Care. Diabetes Care. 2014;37(suppl 1):S25. Figure 1.

Adapted with permission from Ismail-Beigi F, et al. Ann Intern Med 2011;154:554-559

DCCT Research Group. N Engl J Med. 1993;329:977.Skyler J. Endocrinol Metab Clin North Am. 1996;25:243.

A1C and Microvascular Complications: DCCT R

ela

tive R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

A1C (%)

15

13

11

9

7

5

3

1

6 7 8 9 10 11 12

A1C = glycated hemoglobin; DCCT = Diabetes Control and Complications Trial.

A1C and Complications: UKPDS

UKPDS Group. Lancet. 1998;352:837-853.

A1C = glycated hemoglobin; UKPDS = United Kingdom Prospective Diabetes Study Group.

Mortality and Causes of Death in Diabetes

0

10

20

30

40

50

60

T1DMMale T1DMFemale T2DMMale T2DMFemale

Un

der

lyin

gca

use

of

dea

th(

%)

CVD

Cancer

Diabetes

Renal

Others

Morrish NJ, et al. Diabetología. 2001;44:S14-S21.

CVD = cardiovascular disease; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus.

The ABCs of Diabetes Care:Recommended Goals

• A1C

– ADA and IDF recommend < 7.0% in general, < 6.0% in selected individuals.

– AACE/ACE recommend ≤ 6.5% in patients without concurrent serious illness and at low hypoglycemia risk, and > 6.5% in patients with concurrent serious illness and at risk for hypoglycemia.

• Blood Pressure

– AACE/ACE and IDF recommend < 130/80 mm Hg

– ADA recommends <140/90 mm Hg

• Cholesterol

– AACE/ACE and ADA recommend

• LDL-C: < 100 mg/dL (< 70 mg/dL in very high risk patients)

• HDL-C: > 40 mg/dL in men and > 50 mg/dL in women

• Non–HDL-C: < 130 mg/dL (< 100 mg/dL in high-risk patients)

• Triglycerides: < 150 mg/dL

American Diabetes Association. Diabetes Care. 2016;39 Suppl 1:S1-102; Handlesman Y et al. Endocr Pract. 2015; 21 Suppl 1:1-87; IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf

A1C = glycated hemoglobin; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; ADA = American Diabetes Association; HDL-C = high density lipoprotein-cholesterol; IDF = International Diabetes Federation; LDL-C = low density lipoprotein-cholesterol.

Prediabetes Treatment Algorithm

T2DM = type 2 diabetes mellitus

BP = blood pressure

CVD = cardiovascular disease

TZD = thiazolidinedione

GLP-1 RA= glucagon-like peptide-1 receptor agonist

• Weight-loss agents orlistat, lorcaserin, phentermine/topiramate and liraglutide can prevent progression to T2DM

– Improve BP, triglycerides, and insulin sensitivity

• Metformin and acarbose can reduce progression to T2DM by 25% - 30%

– Use for prediabetes is off-label

– Both are safe, confer CVD risk benefit; metformin is well tolerated

• TZDs prevented progression to T2DM in 60% - 75% of patients in clinical trials

– Associated with adverse outcomes

• GLP-1 receptor agonists may be as effective as TZDs

– Promote weight loss, but inadequate safety data

Garber A et al. Endocr Pract. 2008;14 (7)933-946AACE/ACE Diabetes Algorithm Endocr Pract.

2017,doi:10.4158/EP161682.CS; AACE/ACE Obesity Algorithm Part 2

The Ticking Clock

Increased risk for both microvascular and macrovasculardisease begins early in the prediabetic state

– Insulin resistance is already present in patients with NGT who later develop T2DM

– Patients with prediabetes already have insulin resistance and significantly decreased beta-cell function

– Diabetic retinopathy, peripheral neuropathy, and nephropathy occur in patients with prediabetes

– Patients with prediabetes have a 2- to 3-fold increase in CHD risk, similar to patients with diabetes

CHD = coronary heart disease; NGT = normal glucose tolerance; T2DM = type 2 diabetes mellitus

AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016. Endocr Pract. 2016;22(1):84-113;

DeFronzo RA et al. Am J Cardiol. 2011;108(3 Suppl):3B-24B

AACE Diabetes Algorithm

• Guide therapy based on A1C level– Focus on lifestyle intensification at all levels

• Important tenets:

– Target A1C is ≤6.5%• For patients without concurrent serious illness and at low hypoglycemic risk

• Based on associated lower risk of micro- and macrovascular complications

• Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved

• Individualize A1C target based on comorbidities

• Patient should monitor fasting and postprandial blood glucose levels

– Use agents with maximal efficacy, associated with lowest risk of hypoglycemia• Sulfonylureas are therefore much lower in algorithm

• Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia

A1C = glycated hemoglobin; DPP-4 = dipeptidyl-peptidase 4

AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2017. Endocr Pract.

2017,doi:10.4158/EP161682.CS.

Current Antihyperglycemic Medications

Sulfonylureas

Generalized

insulin

secretagogue

12 Groups with Different Mechanisms of Action

-Glucosidase

Inhibitors

Delay CHO

absorption

Biguanide

Reduce hepatic

insulin

resistance

TZDs

Reduce

peripheral insulin

resistance

Amylin Analog

Suppress

glucagon

GLP-1 Analogs

Stimulate cells,

suppress

glucagon

Colesevelam

Bile acid

sequestrant

Bromocriptine

Hypothalamic

pituitary reset

Insulin

Replacement

Therapy

SGLT-2

Inhibitors

Block renal

glucose

reabsorption

Glinides

Restore

postprandial

insulin

patterns

DPP-4 Inhibitors

Restore

GLP-1 Level

Clinical Considerations

• Combining therapeutic agents with different modes of action may be advantageous

• Use insulin sensitizers such as metformin and/or TZDs as part of the therapeutic regimen in most patients (unless contraindicated or intolerance to these agents has been demonstrated)

• Insulin and secretagogues are the only medications that cause significant hypoglycemia– Therefore, dosage of secretagogues or insulin should be adjusted as

blood glucose levels decline, when used in combination with metformin, TZD, DPP-4 inhibitors, and/or incretin mimetics (GLP-1 agonists)

DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; TZD = thiazolidinediones.

AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016. Endocr Pract. 2016;22(1):84-113.

Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; 2010. Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb;

2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals. 2011.

Summary

• Obesity as a disease• Obesity and medical complications• Relationship to diabetes• Prediabetes• Early intervention: prevention or delay of diabetes• Diabetes and related complications

• Treating the ABCs of diabetes

The purpose of AACE Primary Care Day:

We can do better

We must do better