Understanding Pre-Diabetes: Its Diagnosis, Management & Cardiovascular Risk Implication

Yehuda Handelsman, MD, FACP, FACE, FNLAMedical Director & Principal Investigator

Metabolic Institute of America

Amway Grand Plaza Hotel, Grand Rapids, MI, Saturday, 10/6/12 Yehuda Handelsman, M.D., F.A.C.P., F.A.C.E., F.N.L.A

Michigan AACE Annual Meeting October 5-7, 2012

Yehuda Handelsman, MD, FACP, FACE, FNLA

Medical Director & Principal investigator

Metabolic Institute of America

IP-President

American Association of Clinical Endocrinologists

Program Chair & Director

10 World Congress on Insulin Resistance Diabetes & CVDNovember 1-3, 2012, Los Angeles, CA

Solo practice

Endocrinology, Diabetes & Metabolism

Tarzana, California

Handelsman DisclosuresSpeaker’s Bureau- Amylin, Astra Zeneca, BI, BMS, DSI, GSK, Novo-

Nordisk, Santarus

Consultant - Amylin, Amarin, DSI, Gilead, Halozyme, liposcience, Merck, Novo-Nordisk, Sanofi, ResMed, Santarus

Research grant- BI, DSI, Conjuchem, GSK, Lexicon, Merck, Novo Nordisk, Sanofi, Takeda, Xoma, Tolrex

IP-President- American Association of Clinical Endocrinologists

Associate Editor- Journal of Diabetes

Dr Handelsman & his immediate family do not have ownership interest & or stocks of any Pharmaceutical or device company.

Should this lecture include investigational products and non approved FDA treatments & medications’ indication, it would be identified appropriately.

Ht 5’8”, Wt 212 lb

• BMI 32.5

• Triglycerides 166

• HDL-C (mg/dL) 38

• LDL-C 127

• BP 133/≥87

• A1C 5.9

• Fasting glucose 98

• 2hr post 75gr glu 148

Dean 42 y o male, Married 2 kids, systems Analyst. Mother- HTN, DM 2,

Father- CVD

Comment: No individual component is recommended for treatment

Source: Behavioral Risk Factor Surveillance System, CDC.

2000

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 2000, 2010

(*BMI ≥≥≥≥30, or about 30 lbs. overweight for 5’4” person)

2010

1990

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

One in six United States youths is now overweight.

Mann CC. Science. 2005;307(5716):1716-1717.

Energy intake

Ingestion of:

Proteins

Fats

Carbohydrates

Energy expenditure

Physical activity

Diet-induced thermogenesis

Basal metabolic rate

Body weight

Increase Decrease

Energy Homeostasis

Average Weight (lbs) of 5’8” Men in

the United States From 1857-1991W

eig

ht

(lb

s)

Years

175

170

165

160

155

150

145

140

Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 2004;53(4):80-82. Copyright © 2004 United States Centers for Disease Control.

United States Trends in Caloric Intake: NHANES

0

500

1000

1500

2000

2500

3000

kc

als Men

Women

After a two year visit to the United States, Michelangelo’s David is returning to Italy<..

Statue Returns to Italy

His proud sponsors in the USA were:

Technology Progress and the Obesity Epidemic

Adapted from Badman MK, et al. Science. 2005;307(5717):1909-1914.

GI tract

Adipose tissue

Pancreatic islets

Hypothalamus

Hindbrain

CCK

Adiponectin

Insulin

Amylin

Leptin

OXM

Ghrelin

GLP-1

PYY3-36

GIPPP

ResistinVisfatin

Vagal afferents

Multi-Hormonal Control of Body Weight: Role Of Fat-, Gut-, and Islet-Derived Signals

Complex Regulation of Weight and Energy

Central signals

Inhibitalpha-MSH

CRH/UCN

GLP-1

CART

NE

5-HT

Food intakeGut and liver

Pancreas

Autonomicnervoussystem

Energy expenditure

Adipose tissue

Adapted from Campfield LA, et al. Science. 1998;280(5368):1383-1387. Porte D Jr, et al. Diabetologia. 1998;41(8):863-881.

Adrenal cortex

Energy balance

and adipose stores

Meal size

Adrenal steroids

Leptin

Amylin

insulin

External factorsFood availability,

Palatability

Adiponectin

• Ghrelin

• GLP-1

• CCK

• VagusAff

ere

nt

sig

nals

Effe

ren

t sig

nals

NPY

AGRP

galanin

endocanna

orexin-A

Ddynorphin

Stimulate

Overweight

Data are from 1 million men and women (average age, 57 years) followed for 16 years who never smoked and had no history of disease at enrollment.

Normal Weight Obese

Rela

tive R

isk o

f C

ard

iovascula

r D

isease M

ort

alit

y

0.6

3.0

2.62.21.81.41.0

>18 25 30 >40

BMI, kg/m2

Women

Men

Adapted from Calle EE, et al. N Engl J Med. 1999;341:1097-1105.

Overweight and Obesity Increase the Risk of Cardiovascular Disease Mortality

Pulmonary disease

abnormal function

obstructive sleep apnea

hypoventilation syndromeNonalcoholic fatty liver disease

steatosis

steatohepatitis

cirrhosis

Coronary heart disease

Diabetes

Dyslipidemia

Hypertension

Gynecologic abnormalities

abnormal menses

infertility

polycystic ovarian syndromeOsteoarthritis

Skin

Gall bladder diseaseCancer

breast, uterus, cervix

colon, esophagus, pancreas

kidney, prostate

Phlebitis

venous stasisGout

Idiopathic intracranial hypertension

Stroke

Cataracts

Severe pancreatitis

Medical Complications of Obesity

Reaven, 1988

− Several risk factors (eg. dyslipidemia, hypertension, and hyperglycemia) commonly clustered together

− Clustering of risk factors was called Syndrome X

− Recognized Syndrome X as a risk factor for cardiovascular disease

− Postulated that the underlying pathophysiologic mechanism was insulin resistance

Syndrome X

Reaven, 2005Definition and Dietary Approaches to Treatment

Although the majority of insulin-resistant individuals are able to maintain the level of compensatory hyperinsulinemia needed to prevent the development of a significant degree of hyperglycemia, the combination of insulin resistance and hyperinsulinemia greatly increases the likelihood of developing a cluster of closely related abnormalities and the resultant clinical diagnoses that can beconsidered to make up the insulin resistance syndrome

The Insulin Resistance Syndrome

NCEP ATP III/AHA 2001/2005

Metabolic Syndrome- Diagnosis: 3 of 5

Risk factor Defining level (AHA 2005)

• Abdominal obesity (in) Waist:

Men >40

Women >35

• Triglycerides (mg/dL) ≥150 (or Med)

• HDL-C (mg/dL)

Men <40 (or Med)

Women <50

• BP (mm Hg) ≥130/≥85 (or Med)

• Fasting glucose (mg/dL) ≥110 (100)NCEP ATP III. JAMA. 2001;285:2486-97. (Circulation September 2005)

Type 2 diabetes and glycemic disorders

Dyslipidemia

– Low HDL

– Small, dense LDL

– Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis

↑↑↑↑ PAI-1

Ath

ero

scle

rosis

Insulin

resistance

Glucotoxicity

Lipotoxicity

↓↓↓↓ Adiponectin

Courtesy of Selwyn AP, Weissman PN.

Clinical Manifestations of Insulin Resistance

Adiposetissue

↑ IL-6

↓ Adiponectin

↑ Leptin

↑ TNFα

↑ Adipsin(Complement D)

↑ Plasminogenactivator inhibitor-1

(PAI-1)

↑ Resistin

↑ FFA

↑ Insulin

↑ Angiotensinogen

↑ Lipoprotein lipase

↑ Lactate

Inflammation

Type2 diabetes

Hypertension

Atherogenicdyslipidemia

Thrombosis

Atherosclerosis

Lyon CJ, Law RE, Hsueh WA. Endocrinology 2003;144:2195-200.

Trayhurn P, Wood IS. Br J Nutr 2004;92:347-55.

Eckel RH, Grundy SM, Zimmet PZ. Lancet. 2005;365:1415-28.

Adverse Cardiometabolic Effects of Products

of Adipocytes

↑ CRP

0

CRP by No. of Metabolic Disorders(Dyslipidemia, Upper Body Adiposity, HTN, Insulin

Resistance): IRAS (Insulin Resist. Athero. Study)

Festa A et al. Circulation. 2000;102:42–47.

Number of Metabolic Disorders (Nondiabetic)

1 2 3 4

(Suggests increasing levels of CRP are feature of metabolic syndrome)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

Diagnostic Criteria: 3 out of 5Central Obesity

IFG

High TG

Low HDL-C

HTN

Associated ConditionsHyperCoagulability ↑↑↑↑ PAI-1

↑↑↑↑Small, dense LDL-C

Endothelial Dysfunction

Vasculopathy

↑↑↑↑ Sympathetic nervous system activity

↑↑↑↑ Inflammation: CRP, WBCInsu

lin R

esis

tan

ce

Ath

ero

slc

ero

sis

Metabolic Syndrome

Can be found at: http://www.medscape.com/px/urlinfo

Central obesity

Sedentary lifestyle

↓↓↓↓ Physical activity

Increasing age

Genetic factorsFamily History

Population groups

Impaired glucosehomeostasis

Abnormal FFA,VLDL and HDLmetabolism+ visceral fat deposition

Abnormal vascularSMC, medial and endothelial function

Hemostaticabnormalities

Vascularinflammation

Impaired glucose toleranceIGT - IFG

High TGLow HDL

Atherosclerosis

Hypertension

Insulin Resistance

Insulin Resistance

Metabolic- Insulin Resistance- Syndrome

Diabetes

Stroke

PVD

CAD

NASH

PCOS

Hyperuricemia

Metabolic and Vascular

abnormalities

Metabolic and Vascular

abnormalities

Clinical

consequences

Clinical

consequences

Factors Contributing

to Insulin Resistance

Factors Contributing

to Insulin Resistance

Kendall DM and Harmel AP. Am J Manag Care 2002; 8:S635–S653.

Relation of Degree of Insulin Resistance to the Metabolic Syndrome

0

2

4

6

8

10

12

14

16

18

0 1 2 3 4 5

Number of Components of Metabolic Syndrome

HO

MA Insulin R

esis

tance Index

Solymoss et al. Am J Cardiol 2004;93:159-164

Clinical Syndromes Associated

with Insulin Resistance/Hyperinsulinemia

Pediatrics

Non Alcoholic Fatty Liver Disease (NAFLD/NASH)

Polycystic Ovarian Syndrome (PCOS)

Skin

Brain

Certain cancers

Sleep/breathing Disorders

Coagulation

Dyslipidemia

Essential Hypertension

Chronic Kidney Disease

Cardiovascular Disease

Congestive Heart Failure

Type 2 Diabetes mellitus

Insulin Resistance Sleep & BreatingDisturbances are Associated with • ↑ Obesity

• ↑ BP

• ↑ triglycerides, ↓ HDL

• ↑ inflammatory cytokines

• ↑ glucose intolerance

• Stimulation if the HPA axis (3,4)

• ↑ SNS activity (5, 6)3. Vgontzas, AN et al. Clin Endocrin. 51:205-215, 1999

4. Vgontzas, AN et al. JCEM. 86:1387-3794, 2001

5. Somers, VK et al..J Clin Invest. 96:1897-1904, 1995

6. Leunberger, U. j Applied Physiol. 79:581-588, 1995

Coronary Atherosclerosis In Youth Is Linked To Obesity and Insulin Resistance

Fatty StreaksMen: Age 15-24

BMI (kg/m2)

> 3025-30< 25

Raised LesionsMen: Age 15-24

0-2 2-4 4-6 6-8 8-10 10+

Adiposity Index Category HDL

mg/dL

Glycohemoglobin

%

Smoking prevalence

HTN prevalence

BMI, kg/m2 <25 55.0+0.8 6.4+0.03 47.9+1.8 12.6+0.9

25-30 53.1+1.1 6.6+0.05 41.3+2.5 11.3+1.2

>30 51.3+1.5 6.8+0.06 30.9+3.1 15.5+1.8

Adapted from: McGill Jr. et al. (PDAY) Circulation. 2002;105:2712-2718

Aortic Strips

Insulin resistance increases risk of chronic kidney disease (CKD)N = 6453 without diabetes

Odds ratio (highest vs

lowest quartiles*)

Chen J et al. J Am Soc Nephrol. 2003;14:469-77.

*Multivariate adjustedCKD = GFR <60 mL/min per 1.73 m2

HOMA-IR = Homeostasis model assessment of insulin resistance

P = 0.001

P = 0.008

Hypertension and Insulin Resistance

� Nondiabetic patients

(n=13, 47 y) with essential HTN (151/94

mm Hg) vs normotensive men (n=26)

matched for age and BMI

� Insulin sensitivity reduced, but output

increased

|

150

|

0

|

30

|

60

|

90

|

120

|

180

I I I I I I

T

T T TT

T

12—10.5—

9—7.5—6—

4.5—3—

-

--

--

--

--

--

-

Normotensives

Hypertensives

Glucose (mmol/L)

PA

I-1 A

ntigen (

ng/m

L)

35

30

25

20

15

10

5

0Normal glucose

tolerance

(n = 693)

Impaired glucose tolerance(n = 348)

Type 2

DM(n = 510)

Festa A et al. Arterioscler Thromb Vasc Biol. 1999;19:562-568.

Reproduced with permission from Lippincott, Williams and Wilkins.

PAI-1 Levels and Glucose Tolerance

The Dyslipidemia of Insulin Resistance

Elevated

TG

Small, dense

LDL-CLow HDL-C

CHD

Insulin Responses to a 75-g OGT in 100 Non-Diabetic Healthy, Normal, Subjects in Relation to LDL Phenotype Pattern [ A, Intermediate (AB) or B ]

Reaven GM et al.

J Clin Invest.

1993;92:141-146.

1000

800

600

400

00 30 60 90 120 150

200

Time (min)Pattern B Pattern AIntermediate (AB)

Small dense LDL (Pattern B Dyslipidemia) is

Strongly Associated with Insulin Resistance

Same LDL-C Levels, Different Cardiovascular Risk

Apo B

LDL= 130 mg/dLFewer Particles More Particles

Cholesterol

Ester

More Apo B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

Correlates with:

TC 198 mg/dL

LDL-C 130 mg/dL

TG 90 mg/dL

HDL-C 50 mg/dL

Non–HDL-C 148 mg/dL

Correlates with:

TC 210 mg/dL

LDL-C 130 mg/dL

TG 250 mg/dL

HDL-C 30 mg/dL

Non–HDL-C 180 mg/dL

Increased insulin resistance is associated with

increased CVD risk: San Antonio Heart Study

Odds ratio for risk of CVD (95% CI)

Quintile 5

Quintile 4

Quintile 3

Quintile 2

0 1 2 3 4 5

HO

MA

IR

Qu

inti

les

Association between HOMA-IR and 8-year risk of CV outcomes (CV death, MI, CABG, CVA, angina) in 2600 subjects free of DM and CVD at baseline

Adapted from Hanley AJ, et al. Diabetes Care 2002; 25:1177–1184.

Quintile of HOMA-IR adjusted for age, sex, ethnicity, LDL, triglyceride, HDL, systolic blood pressure, smoking, alcohol consumption, leisure time exercise and waist circumference (median split) P (trend) = 0.0185

CHD Mortality

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.77 (1.74-8.17)

Follow-up (y)

Cu

mu

lati

ve H

azard

(%

)

Yes

No

866

288

852

279

834

234

292

100

The Kuopio Ischemic Heart Disease

Prospective 1209 Finnish men, age 42 to 60 from 1984−1989

No. at Risk

Metabolic Syndrome

YesMetabolic Syndrome:

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.55 (1.96-6.43)

Follow-up (y)

866

288

852

279

834

234

292

100

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 2.43 (1.64-3.61)

Follow-up (y)

866

288

852

279

834

234

292

100

CVD Mortality All-Cause Mortality

Lakka HM et al. JAMA. 2002;288:2709-2716.

No

CI, confidence interval; RR, relative risk.

Risk for All-Cause Mortality and Glucose Control: A Continuum Not a Threshold

EPIC-Norfolk Study

0

1

2

3

4

5

6

7

<5 5–5.4 5.4–6.9 >7 Known DM

HbA1c (%)

Adapted from Khaw K-T et al. BMJ. 2001;322:1-6.

All-c

au

se

Mo

rta

lity

* (%

)

* Age-adjusted

Insulin resistance to diabetes: Coronary vasomotor abnormalities progressively worsen

Prior JO et al. Circulation. 2005;111:2291-8.

*vs baseline

†P < 0.05 vs insulin sensitive

Cold pressor test

Insulinsensitive

Insulinresistant

IGT

Diabetes +

Hypertension

–10

0

10

20

30

40

14 7

Diabetes

10

–2

44

∆

MBF* (%)

†

††

†

IGT and undiagnosed DM2 are common in acute MI and stroke

Norhammar A et al. Lancet. 2002;359:2140-4.Matz K et al. Diabetes Care. 2006;792-7.

2-hour OGTT

66

39

(n = 181) (n = 238)

Myocardial infarction Stroke

IGT Undiagnosed DM2

Only 20% of stroke and 34% of MI patients had normal glucose levels.

MANAGEMENT

Ht 5’8”, Wt 212 lb

• BMI 32.5

• Triglycerides 166

• HDL-C (mg/dL) 38

• LDL-C 127

• BP 133/≥87

• A1C 5.9

• Fasting glucose 98

• 2hr post 75gr glu 148

Dean 42 y o male, Married 2 kids, systems Analyst. Mother- HTN, DM 2,

Father- CVD

Comment: No individual component is recommended for treatment

< 25 Lifestyle/Meds

< 100 mg/dL 1st * Statins

< 150 mg/dL 2nd * Fibrates

> 40 mg/dL 2nd * Niacin> 50 mg/dL Fibrates

< 130/85 mmHg TLM/ACE/ARB

< 100 mg/dL } TLM/meds

< 140 mg/dL } TLM/meds

Goals TreatmentParameters

BMI

LDL

TGs

HDL-CMenWomen

BP

FG

PP glucose

Metabolic Syndrome Goals & Treatment of Components

NCEP ATP III. JAMA. 2001;285:2486-2497.

*Treatment. of dyslipidemia: LDL-C is primary goal; may treat secondary goals (ie, TG, HDL-C).

ARB, angiotensin receptor blocker; ACE, angiotensin converting enzyme;

Therapeutic Lifestyle Modification (TLM); TZD, thiazolidinedione.

Goals TreatmentParameters

Dean : Obesity

BMI : 32.5

Treatment : NoneConsider : Lifestyle & Intervention

Medications

*Years 0/1/2 : Significantly different from the corresponding timepoints, P<0.0001.

+All measures significantly different from baseline and each other, P<0.0001.

Adapted from Despres J. Presented at ADA 2009 Symposium; June 5-9, 2009, New Orleans, LA.

SYNERGIE: Weight Loss and

HDL Cholesterol Over 3-Year Study

Body weight in men, followed for 3 yrs

HDL cholesterol in men,followed for 3 yrs

4

2

0

-2

-4

-6

Re

du

ctio

n in

bo

dy

w

eig

ht

(kg

)

Follow-up (yrs)

1 2 3

**

*

0 0/1 0/1/2Follow-up (yrs)Baseline

0 1 2 3

1,2

1,1

1,0

++

+

HD

L ch

ole

ste

rol

(mm

ol/

L)

TC : 189 mg/dL

LDL: 112 mg/dL

HDL: 42 mg/dL

TG : 175 mg/dL

Med: Atorvastatin 40mg

Consider: Combination Medication

Dean: Lipid Control

Isolated ↑↑↑↑ LDL-CRR=0.86 (0.59–1.26)

221

Metabolic Syndrome- LDL CVD in 4SEvent Rate (%)

Ballantyne CM et al. Circulation. 2001;104:3046-3051.

Simvastatin

Placebo

237 261 284

18.020.319.0

Lipid TriadRR=0.48 (0.33–0.69)

0

10

20

30

4036.9

4S, Scandinavian Simvastatin Survival Study.

Deedwania P et al. Lancet 2006;368:919-928.

TNT: Risk for Major CV Event in Patients with

Metabolic Syndrome

BP: 138/87 mm Hg

Urinary albumin: 100 mcg/min

Med: None

Consider: ACE or ARB (navigator trial:

Valsartan reduced progression to DM 14%)

Dean: Blood Pressure Control

A1C 5.9

Fasting glucose 98

2hr post 75gr glu 148

Med: None

Consider: Recommend Lifestyle

Dean: Glucose Control

Metformin Effect on

Cardiovascular Risk Factors

CVRF Metformin

1. Hyperglycemia

2. Hypertriglyceridemia

3. Hypercholesterolemia

4. Obesity

5. Hyperinsulinemia

6. Insulin Resistance

7. PAI-1

8. Endothelial Dysfunction

TZD Effects on Lipids

Week 24 Change From Baseline

PIO ROSI P value

Triglycerides -12.0% +14.0% <.001

HDL-C +14.9% +7.8% <.001

LDL-C +15.7% +23.3% .002

FFA (mEq/l) -0.11 -0.12 0.681

A1C -0.7% -0.6% 0.129

FPG (mg/dL) -33.2 -36.6 0.233

• Significance of data pending

– Peer-review publication of trial

• Clinical outcomes data

• TZD use with statinsGoldberg R et al. Diabetes Care. 2005;28:1547-1554.

Body weight reduction from baseline over

20 weeks in obese people without diabetes

–8

–7

–6

–5

–4

–3

–2

–1

0

–9

-5 -3 0 5 10 15 20Time (weeks)

Mean weight loss (kg)

Screening

Randomisation

Liraglutide 1.2 mg OD Liraglutide 1.8 mg OD

Liraglutide 2.4 mg OD Liraglutide 3.0 mg OD Orlistat 120 mg TID

Placebo

Baseline body weight (kg)

97.3

96.2 98.0

98.4

97.6

96.0

Liraglutide is not indicated for weight loss and not for use in people without diabetesAstrup et al. Lancet 2009;374:1606–16

OD, once daily; TID, three-times daily

Exenatide for 3.5 y

Study Results

Parameter

Baseline

(Mean ± SD)

Change from Baseline

(Mean ± SE) Average of % Change

Triglycerides (mg/dL) 225 ± 142 -44.4 ± 12.1 -12%

Total cholesterol (mg/dL) 184 ± 37 -10.8 ± 3.1 -5%

HDL-C (mg/dL) 39 ± 10 +8.5 ± 0.6 +24%

LDL-C (mg/dL) 114 ± 33 -11.8 ± 2.9 -6%

SBP (mmHg) 129 ± 13 -3.5 ± 1.2 -2%

DBP (mmHg) 79 ± 8 -3.3 ± 0.8 -4%

SD=standard deviation; SE=standard error; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; SBP=systolic blood pressure; DBP=diastolic blood pressure

Kendall D, et al. Abstract 557-P. Poster Presentation, 67th Scientific Sessions ADA 2007

•*All changes from baseline statistically significant

In Summary <

� Many aspects of insulin Resistance Metabolic Syndrome are modifiable with pharmacologic tools when lifestyle changes are not successful enough.

� There are currently no “approved” drugs for the insulin and glucose abnormalities of this syndrome in the absence of diabetes.

� The decision to “treat” patients prior to overt diabetes or to “reduce” the risk of CVD is currently one of individual clinical judgment.

� For patients with the pre diabetes- Metabolic Syndrome- a recent consensus position of the American Association of Clinical Endocrinnologists(AACE) recommends management of these patients with life style modifications and medication to prevent diabetes and reduce CV risk

Ag

e-a

dju

ste

d r

ela

tiv

e r

isk

Body mass index (BMI) (kg/m2)

Men

Women

<22 <23 23-

23.9

24-

24.9

25-

26.9

27-

28.9

29-

30.9

31-

32.9

33-

34.9

35+

1.0

2.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.711.6

21.3

42.1

0

25

50

75

100

Chan JM, et al. Diabetes Care. 1994;17(9):961-969.

Colditz GA, et al. Ann Intern Med. 1995;122(7):481-486.

Relationship Between BMI andRisk of Type 2 Diabetes

June 25, 2001

The Diagnosis and Management of

Pre-Diabetes in the Continuum of

Hyperglycemia—

When Do the Risks of Diabetes Begin?

American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) CONSENSUS

STATEMENT

Why Recommendations for Pre-Diabetes?

57 million people in the US have pre-diabetes

Worldwide, number of people with pre-diabetes is estimated at 314 million

Projected to be418million worldwide by 2025

Pre-diabetes raises the short-term absolute risk of type 2

diabetes by 3- to 10- fold, with some populations exhibiting

greater risk than others.

Risk of Complications in Type 2 Diabetes

0

1

2

3

4

5

5.5 6.5 7.5 8.5 9.5

HbA1c

P<.0001

21% risk decrease per 1% decrement in HbA1c

*Reference category (hazard ratio 1.0) is HbA1c <6% with log linear scales. Data adjusted for age at

diagnosis of diabetes, sex, ethnic group, smoking, presence of albuminuria, systolic blood pressure,

high and low density LDL and triglycerides.

Adapted from Stratton IM, et al. (UKPDS 35). BMJ. 2000;321:405-412.

Any End Point Related to Diabetes*

Every Single Day in the United States<.

� 5,205 new cases of diabetes are diagnosed

� 230 people have a diabetes-related

amputation

� 133 people with diabetes progress to end-

stage renal disease

� 55 people with diabetes become blind

Centers for Disease Control and Prevention. 2011 National Diabetes Fact Sheet: Diagnosed and undiagnosed diabetes in the United States, all ages, 2010. Atlanta,

Age-adjusted Percentage of U.S. Adults

with Obesity or Diagnosed Diabetes Obesity (BMI ≥30 kg/m2)

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

2009

2009DIABETES

DIABETES

2000 2009OBESITY

OBESITY

DIABETES

DIABETES

Prediabetes

state

Normal IGT

Clinical

disease

Type 2

DiabetesDisability

Death

Complications

Complications

Primary Secondary Tertiary

prevention prevention prevention

Type 2 Diabetes:

A Progressive Disease

79,000,000 26,000,000

Garber AJ, Handelsman Y, Einhorn D, et al. Endocr Pract. 2008;14:933-46.

http://www.cdc.gov/media/releases/2011/p0126_diabetes

0

1

2

3

4

5

6

7

8

<5% 5-5.4% 5.5-5.9% 6-6.4% 6.5-6.9% ³7 DM

Men Women

Data from Khaw KT, et al. Ann Int Med. 2004;141(6):413-420.

Ag

e-a

dju

ste

d R

R

P<0.001 for linear trend across A1C categories for all endpoints.

A1C and Coronary Risk in the EPIC Study

Thom T, et al. AHA. Circulation. 2006;113(6):e85-e151.

Centers for Disease Control. http://www.cdc.gov/nchs/nhis.htm. Accessed March 25, 2010.

National Hospital

Discharge Survey

CVD

Dis

ch

arg

es (

mil

lio

ns)

90 0300950

4

5

6

7

Year

Nu

mb

er

(mil

lio

ns)

National HealthInterview Survey

Diabetes

90 04989492 0096 02

Year

↑↑↑↑119%

CVD Has Risen, Accompanied by Diabetes

Macrovascular Microvascular

Cerebrovascular

disease

Heart disease and hypertension

Ulcers and

amputation

Diabetic eye disease(retinopathy, cataracts

macular edema)

Renal disease

Peripheral

Neuropathy

Foot problems

Peripheral vascular disease

Diabetes Complications

Erectile dysfunction

Autonomic

Neuropathy

9.8 9.5 9.17.9

6.6

27.8

22.9

18.9

1.8 1.7 2.11.1 1.8

6.1

10

0

10

20

30

Heart attack Chest pain Coronary

heart

disease

Congestive

heart failure

Stroke Chronic

kidney

disease

Foot

problems

Eye damage

Perc

en

tag

e w

ith

co

mp

licatio

ns Diagnosed diabetes

Normal blood sugar levels

Prevalence of Diabetes Macrovascular and Microvascular Complications

Macrovascular Microvascular

American Association of Clinical Endocrinologists. State of Diabetes Complications in America Report. Available at:

http://www.aace.com/newsroom/press/2007/images/DiabetesComplicationsReport_FINAL.pdf. Accessed April 18, 2007.

*

†

Z

*In NHANES, “chronic kidney disease" refers to people with microalbuminuria (albumin:creatinine ratio >30 µg/mg).†In the NHANES analysis, "foot problems" includes foot/toe amputations, foot lesions, and numbness in the feet.‡"Eye damage" includes a positive response by NHANES participants to the question, "Have you been told diabetes has affected your eyes/had

retinopathy?" Retinopathy is damage to the eye's retina. In NHANES, people without diagnosed diabetes were not asked this question, therefore,

prevalence information for nondiabetics is not available.

NORMAL IFG or IGT High Risk

for DM

DIABETES

FPG < 100 mg/dl IFG

FPG > 100 - 125 mg/dl

FPG > 126 mg/dl

2-h PG < 140 mg/dl IGT

2-h PG > 140 -

199 mg/dl

2-h PG > 200 mg

Random PG > 200 +

symptoms

A1C 5.5% to 6.4%

For screening *

(ADA 5.7% to 6.4)

≥ 6.5%

Secondary **

(ADA Primary)

AACE & ADA 2010 Diagnosis of Diabetes & Pre DM

ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

* Requires testing FG or GTT ** Confirm with Glucose when possible

1. A1C is considered optional not primary criterion for diagnosis of diabetes.

2. AACE suggests glucose criteria when feasible.

3. A1C is not for diagnosing type 1 diabetes.

4. A1C is not for diagnosing gestational Diabetes.

5. A1C may be misleading in several ethnic populations (i.e, African American).

6. A1C may be misleading in hemoglobinopathies, iron deficiency, hemolytic anemia, thalassemias, spherocytosis and severe hepatic and renal disease.

A1C For Diagnosis- Precaution

ENDOCRINE PRACTICE Vol 16 No. 2 March/April 2010 155-6

Interventions Proven to Delay or

Prevent Type 2 Diabetes

Intervention % Risk Reduction

Lifestyle (4 trials) 29-58%

Metformin (2 trials) 26-31%

Lifestyle & Metformin (1 trial) 28%

Acarbose (1 trial) 25%

Troglitazone (1 trial) 52%

Rosiglitazone (1 trial) 62%

Pioglitazone (2 trials) 72%

Ht 5’10”, Wt 243 lb

• BMI 35

• Triglycerides 287

• HDL-C (mg/dL) 34

• LDL - 108

• BP 138/≥83

• A1C 6.3%

• Fasting glucose (mg/dL) 118

2hr post 75gr glu 186NCEP ATP III. JAMA. 2001;285:2486-97.

Mike

37 y male, Married 2 kids, computer programmer, C/0 E.D,

Mother- HTN, CVD. Father- DM2, CVD

Glu

co

se

(mg

/dL

)R

ela

tive f

un

cti

on

-10 -5 0

50

100

150

200

250

300

350

Insulin Resistance

Changes in Insulin Levels

Elevations in Fasting Glucose (IFG)

Elevations in Post-meal Glucose (IGT)

Onset

Diabetes

Onset

Diabetes

Pre Diabetes

Metabolic Syndrome

0

50

100

150

200

250

-15

Impaired Incretin Action

Years

Progression to Type 2 Diabetes

Impaired Glucose

Tolerance

Impaired Fasting Glucose

Diabetes

Stages in the History of

Type 2 Diabetes

Or Both

Relative Risk of Developing Diabetes Based on IGT and IFG Status

Haffner SM. Unpublished Data. IRA study.

The Metabolic Syndrome Raises the Risk for Diabetes

1.0

5.0

10.0

20.0

25.0

MetS

without

IFG

IFG

without

MetS

MetS

+

IFG

Lorenzo C, et al. Diabetes Care. 2007;30:8-13

No MetS

No IFG

Odds

Ratio

(Confidence

Interval)5.03

(3.39–7.48)

21.0 (13.1–33.8)

7.07 (3.32–15.1)

1.0

(ref)

Normal Fasting Plasma Glucose and Risk of Type 2 Diabetes Diagnosis

• The following increase the risk of developing

diabetes associated with normal fasting plasma

glucose

– Obesity

– Hypertension

– Low HDL cholesterol

– High triglycerides

– Smoking

• Closer surveillance for diabetes development might

be warranted in these patients

Nichols GA, et al. Am J Med 2008;121:519-524.

Risk Factors for Pre-DiabetesCardiovascular

Disease

Family History of Diabetes

Hypertension

DyslipidemiaSedentary

lifestyle

Overweight or Obese

Non-Caucasian Ancestry

Previously identified IGT, IFG, and/or metabolic syndrome

History of Gestational Diabetes

Delivery of a large baby

(>9 lbs/ 4 kg)

Polycystic ovary disease

Treatment for schizophrenia

or bipolar disease

Clinical Risks of Not TreatingPre-Diabetes are Substantial

• These complications involve both microvascular disease

– Retinopathy

– Neuropathy

– Nephropathy

• And cardiovascular disease (CVD)

– Heart disease

– Stroke

– Peripheral vascular disease

Most diabetes patients

die of CVD

Wong TY, et al. Lancet 2008; 371: 736–43

Fasting Plasma Glucose Thresholds Above Which the Prevalence of Retinopathy Increases

Blue Mountains

Eye Study

Australian

Diabetes, Obesity,

and Lifestyle

Study

Multi-ethnic Study

of Atherosclerosis

On visual

inspection

6.3-7.0 mmol/l

(113 -126 mg/dL)

7.1-7.8 mmol/l

(85.2-140 mg/dL)

No clear threshold

Change point

model

5.2 mmol/l

(93.6 mg/dL)

6.3 mmol/l

(113 mg/dL)

No clear threshold

Wong TY, et al. Lancet 2008; 371: 736–43.

Relationship Between Fasting Plasma Glucose and 5-Year Incident Retinopathy

≤83 84-97 99-112 113-126 ≥185128-140 157-169 171-184142-155 Mg/dL

Impaired Glucose Tolerance and Peripheral Neuropathy

• Diabetes is the most common cause of peripheral

neuropathy

• Up to 1/3 of neuropathy patients have no identifiable etiology

– Among this population, IGT is observed in approximately 40% of

patients, suggesting that neuropathy may occur as a result of pre-

diabetes

• Treatment of IGT patients with diet and exercise reduces the

risk of progression to diabetes and those with neuropathy

experience a short-term improvement in small fiber function,

with sustained benefit for pain

Singleton AG & Smith JR. Neurologist 2008;14:23-29.

Elevated Risk of CVD Prior to Clinical Diagnosis of Type 2 Diabetes

1

2.82

3.71

5.02

0

1

2

3

4

5

6

Nondiabetic

throughout the

study

Prior to diagnosis

of diabetes

After diagnosis

of diabetes

Diabetic at

baseline

Rela

tive R

isk

Hu et al. Diabetes Care. 2002;25:1129-1134.

Hoorn- IFG/IGT – CV risk Summary

Prevalence Diabetes risk CVD risk

IGT 10-15 % > 10 1.5

IFG-WHO 10-15 % > 10 1.2

IFG-ADA 30-40 % 2-3 1.1

• IFG and IGT result from different mechanisms

• Criteria from expert comittees

• publication before evaluation in existing data

Dekker, Balkau. Diabetes Care 2006

CVD and Diabetes Incidence: Relative Risk and Metabolic Syndrome Traits

Metabolic

Traits

Present

EventIFG

Present

IFG

Absent

Two Traits

CVD 1.9-2.6X 1.7-2.2X

Diabetes

Mellitus8.2-10.7X 3.1-5.0X

Three Traits

CVD 1.8-2.4X 1.9-2.1X

Diabetes

Mellitus7.7-12.4X 3.5-5.4X

Wilson Circulation 2005; 112: 3066

Relative risk of mortality is significantly

increased in subjects with IGT

DECODE- Multivariate adjusted: for age, centre, sex, cholesterol, BMI, BP, smoking

Mortality RR, multivariate

adjusted

RR, adjusted

also for FPG

CVD 1.34

(1.14-1.57)

1.32

(1.12-1.56)

CHD 1.28

(1.02-1.59)

1.27

(1.03-1.58)

Stroke 1.26

(0.88-1.80)

1.21

0.84-1.74)

All-cause 1.40

(1.27-1.54)

1.37

(1.25-1.51)

Two-Track Approach to Reduce Risk

• Lifestyle Intervention

• Pharmacotherapy in high risk patients

(1) Lower glucose to prevent microvascular

complications and progression to

diabetes

• Lifestyle Intervention

• Blood pressure goals: <130/80 mm Hg

• LDL goal: <100 mg/dL

(2) Address cardiovascular

disease risk factors

People with Pre Diabetes should be treated to the same CV risk goals as people with Diabetes

BP < 130/80

LDL < 100 (high risk < 70)

TGL < 150

HDL > 40

Consider: Statins, Fibrates, ACE ARBs, ASA etc

Pharmacotherapy for CV Risk Factors

Target Goal First-line agents Comments

LDL ≤100 mg/dL

(≤5.5

mmol/L)

Statins Additional use of fibrates, bile acid

sequestrants, ezetimibe, etc.,

should be considered as

appropriate.

Niacin should be avoided.

Blood

pressure

<130/80

mm/Hg

ACE inhibitors,

Angiotensin

receptor

blockers

Calcium channel blockers are

appropriate second line treatment

approaches.

Beta-blockers and thiazides should

be avoided.

Low-dose aspirin is recommended for all persons with pre-diabetes for

whom there is no identified excess in risk for gastrointestinal,

intracranial, or other hemorrhagic condition.

Elliott WJ, Meyer PM. Lancet 2007; 369: 201–07

Incident diabetes in clinical trials of

antihypertensive drugs: meta-analysis of 22

clinical trials in 143,153 patients

The priority in choice

of BP-lowering drugs• ACE-I/ARBs

– May be renal protective

– Ramipril did not prevent or predispose to diabetes

(DREAM trial)

• Long-acting calcium blockers

• Low-dose thiazide diuretics

– High doses predispose to diabetes (ALLHAT)

• Beta-blockers

– May worsen insulin resistance

Interventions to Reduce the Risks Associated with Pre-Diabetes

and Prevent Diabetes- Manage hyperglycemia

• Intensive lifestyle management is the cornerstone of

all prevention efforts

• No pharmacologic agents are currently approved

for the management of pre-diabetes.

– Pharmacotherapy targeted at glucose may be considered

in high risk patients- 2 out of the 3 IFG, GGT, MetSX-

after individual risk: benefit analysis.

For Patients with Prediabetes/MetS

Should Consider low-dose aspirin

• Efficacy

– Reduces risk for CVD by 20-25%

• Cost

– Not a factor

• Safety

– GI and cerebral hemorrhage

• Efficacy/Safety Ratio

– Positive when 10-yr risk for major CVD events >

10% (Framingham risk scoring)

Lifestyle Intervention

Persons with pre-diabetes should reduce weight by 5-10%, with long-term maintenance at this level.

A diet that includes calorie restriction, increased fiber intake, and maybe limitations in carbohydrate intake is advised.

• A program of regular moderate-intensity physical activity for 30-60 minutes daily, at least 5 days weekly, is recommended.

Interventions Proven to Delay or Prevent Development of Type 2 Diabetes

Intervention % Risk Reduction

Lifestyle (4 trials) 29-58%

Metformin (2 trials) 26-31%

Lifestyle & Metformin (1 trial) 28%

Acarbose (1 trial) 25%

Troglitazone (1 trial) 52%

Rosiglitazone (1 trial) 62%

Pioglitazone (2 trials) 72%

Multifactorial Lifestyle Intervention Reduces Incidence of Type 2 Diabetes in High-risk Groups

1Tuomilehto, J et al. N Engl J Med 20012Knowler et al. N Engl J Med 2002

0

10

20

30

40

50

1 2 3 4 5 6

Years of intervention

Cumulative incidence (%) 58% risk reduction

in lifestyle group

0

10

20

30

40

50

0 1 2 3 4

No intervention

Lifestyleintervention

Years of intervention

Placebo

Lifestyleintervention

58% risk reduction

in lifestyle group

Finnish Diabetes Prevention Study1 US Diabetes Prevention Program2

The Chinese Prevention Study The effect of metformin on the progression

of IGT to diabetes mellitus (n = 321)

Incidence of diabetes (%/yr)

Adapted from: Yang ,W. et al. Chin. J. Endocrinol. Metab. 17: 131-136, 2001

RRR = 65%

Medical Weight Loss Strategies

• There is evidence for orlistat in preventing progression from

pre-diabetes to diabetes.

• Sibutramine is similarly effective to orlistat in reducing weight,

lipids, and glycemic control, but may have adverse blood

pressure effects in some patients that must be considered. And

is no longer available

• Cannabinoid receptor antagonists, although effective in

reducing weight and improving glycemia, may cause anxiety

and depression and are not currently approved in the US.

• Two new medications- Belviq (lorcaserin,) Qsymia

(phentermine &topiramate) were just approved for weight loss

• Bariatric Surgery, Lap-Band

Orlistat Reduces Incidence of Diabetes

Inc

ide

nc

e o

f D

iab

ete

s

4-Yr Xendos Study 3-Yr Danish Study

Torgerson Diab Care 2004;27:155; Richelsen Diab Care 2007;30:27

9%

6.2%

10.9%

5.2%

0

2

4

6

8

10

12 Placebo

Orlistat

S

Adapted from: Knowler, W.C. et al. N. Engl. J. Med. 346: 393-403, 2002

Effect of Lifestyle and Metformin on the

Cumulative Incidence of Diabetes

(n = 3234)

Mather KJ et al. J Am Coll Cardiol. 2001;37:1344-50. * P = 0.0027 vs placebo

Before treatment After treatment

400

300

250

200

150

50

0

350

Metformin 1000 mg

(3 months)

3

Increase in forearm

blood flow (%)

Acetylcholine (µg/min)

100

*

Placebo

10 30 3 10 30

*

*

Metformin improves endothelial function

PAI-1 (AU/mL)

Effect of Metformin on PAI-1 Levels

Nagi DK et al. Diabetes Care. 1993;16:621-629.

*P=0.001 compared with baseline.

†P=0.0001 compared with baseline.

ZP=0.048 compared with 6 weeks.

Treatment duration (weeks)

15

20

25

30

0 6 12

Metformin

Placebo

P=0.001

P =0.036

P=0.096

*

†Z

DPP (73%)

TRIPOD (55%)

ACT NOW (72% )

DREAM (62% )

Studies of Thiazolidinediones to Prevent

Progression from IGT to Type 2 Diabetes

PIPOD (58%)

Antihypertensive Effects of Thiazolidinediones

•Pioglitazone –3 mm Hg –3 mm Hg

•Rosiglitazone–3.5 mm Hg –2.7 mm Hg

•Troglitazone –9 mm Hg –6.5 mm Hg

SBP DBP

Because of concerns about

their long-term safety, use of TZDs should be

reserved for higher risk populations

and those failing other, lower risk strategies.

Effect of Acarbose on the Reversion of IGT to Normal Glucose Tolerance: The STOP-NIDDM Trial

100

120

140

160

180

200

220

240

n = 241(35.3%)

(30.9%)

Hazard ratio = 1.42 (95% CI 1.24 - 1.62); p < 0.0001

Adapted from: Chiasson, J.-L. et al. Lancet 359: 2072-2077, 2002

Placebo Acarbose

n =

212

Effects of acarbose on the number of subjects with

cardiovascular events in the IGT population:

The STOP-NIDDM Trial

0

5

10

15

20

25

30

35

(n = 32) (n = 15)

Adapted from: Chiasson, J.-L. et al. JAMA 290: 486-494, 2003

No. of subjects (n = 47)

p = 0.0326

Placebo Acarbose

ORIGIN- Insulin Glargine

In high risk people with IFG, IGT or early

diabetes, does insulin replacement therapy

targeting fasting normoglycemia (< 5.3 mM or 95

mg/dl) with insulin glargine, reduce CV outcomes

more than standard approaches to dysglycemia?

*P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU.

†All liraglutide dosages shown are 1.8 mg QD.

1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456.

4. Marre M, et al. Diabet Med. 2009;26:268-279. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1232.

6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055.

∆W

eig

ht (k

g)

Weight Reduction With Liraglutide:Mono and Dual Combination Therapy

* ****

*

*

***

Monotherapy vs

Glimepiride

52 Weeks1

Add-on to

Metformin

26 Weeks2

Add-on to

Metformin

26 Weeks3

Add-on to

Sulfonylurea

26 Weeks4

Add-on to

Met + TZD

26 Weeks5

Add-on to

Met + SU

26 Weeks6

N 746 1091 665 1041 821 581

Treatment

(mg/day)

Glim Lir Met Gli +

Met

Lira +

Met

Sit +

Met

Lira +

Met

SU Rosi +

SU

Lira +

SU

Rosi +

Met

Lira +

Rosi +

Met

Met +

SU

Glar +

Met +

SU

Lira +

Met +

SU

*

Preventing the progressionof pre-diabetes to diabetes

is cost effective

Diabetes prevention may have further cost

saving if the cost of lifestyle interventions

becomes lower through the availability of

group or web-based programs and the

coming availability of an expanded number of

generic medications.

Pre-Diabetes Consensus Statement: Summary

• Individuals with pre-diabetes are at increased risk for

diabetes as well as for micro- and macro-vascular

complications

• Treatment goals are to prevent deterioration in glucose

levels and modify other risk factors, such as obesity,

hypertension, and dyslipidemia

– The same BP and lipid goals for pre-diabetes as for diabetes are

suggested

• Intensive lifestyle management is the cornerstone of all

prevention efforts, pharmacotherapy targeted at glucose

may be considered in high risk patients after individual

risk:benefit analysis

Summary- Comprehensive Approach

� The obesity epidemic contributes to diabetes & CVD epidemics

� Target multiple conditions to reduce overall risk

� Utilize lifestyle modification for prevention & treatment

� Institute intensive treatment for glycemic control

� Benefit of LDL-lowering treatment in diabetic patients

� Benefit of ACE/ARB in treatment of HTN in Diabetes

� Consider anti-plateletes treatment to reduce thrombosis risk

� Consider comprehensive care of all risk factors, with combination

medications, to reduce CVD & complications

THANK YOU QUESTIONS?Nava Handelsman

Thank you Questions?