Diabetes Mellitus 101 for Medical Professionals

An Aggressive Pathophysiologic Approach to An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes:Cardiometabolic Therapy for Type 2 Diabetes:

Stanley Schwartz, MD, FACE, FACPEmeritus, Clinical Associate Professor of Medicine, University of Pennsylvania

Affiliate, Main Line Health System, Wynnewood, Pennsylvaniastschwar@gmail.com

6105472000

Part 1

Natural History of Type 2 Diabetes

IR phenotypeAtherosclerosisobesityhypertensionHDL,TG,

HYPERINSULINEMIA

Endothelial dysfunctionPCO,ED

Envir.+ Other Disease

Obesity (visceral)

Poor Diet Inactivity

Insulin Resistance

Risk of Dev. Complications

ETOHBPSmoking

EyeNerveKidney

Beta Cell Secretion

Genes

BlindnessAmputationCRF

Disability

Disability

MICVAAmp

Age 0-15 15-40+ 15-50+25-70+

Macrovascular Complications

IGT Type II DM

Microvascular Complications

DEATHpp>7.8

Natural History of Type 2 Diabetes

IR phenotypeAtherosclerosisobesityhypertensionHDL,TG,

HYPERINSULINEMIA

Endothelial dysfunctionPCO,ED

Envir.+ Other Disease

Obesity (visceral)

Poor Diet Inactivity

Insulin Resistance

Risk of Dev. Complications

ETOHBPSmoking

EyeNerveKidney

Beta Cell Secretion

Genes

BlindnessAmputationCRF

Disability

Disability

MICVAAmp

Age 0-15 15-40+ 15-50+25-70+

Macrovascular Complications

IGT Type II DM

Microvascular Complications

DEATHpp>7.8

Why Bother to Treat Agressively?

One third of adults with diabetes are undiagnosed

~10% of US adults have diabetes/~20 million persons in 2005

Nearly one third don’t know they have diabetes

26% of US adults have impaired fasting glucose (IFG)*

*100–125 mg/dLCowie CC et al. Diabetes Care. 2006;29:1263-8.

NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov.

Total: 35% of US adults with diabetes or IFG~73.3 million persons

Considering the Epidemic of Metabolic Syndrome, Considering the Epidemic of Metabolic Syndrome, Prediabetes, Prevention Data, Undiagnosed Diabetes-Prediabetes, Prevention Data, Undiagnosed Diabetes-

ER Office and Pre-Admission ER Office and Pre-Admission IDENTIFICATION IS CRITICAL!IDENTIFICATION IS CRITICAL!

• Family history: whether parents or siblings have had diabetesFamily history: whether parents or siblings have had diabetes

• Obesity: especially with an increase in abdominal girthObesity: especially with an increase in abdominal girth

• High-risk ethnic group: African Americans, Hispanics,High-risk ethnic group: African Americans, Hispanics,Native Americans, Asians, and Pacific IslandersNative Americans, Asians, and Pacific Islanders

• Age: Age: we’re looking at all ages, if patient seems at riskwe’re looking at all ages, if patient seems at risk

• Impaired fasting glucose or impaired glucose toleranceImpaired fasting glucose or impaired glucose tolerance

• Hypertension: blood pressure ≥ 140/90 mm Hg in adultsHypertension: blood pressure ≥ 140/90 mm Hg in adults

• High density lipoproteins < 35 mg/dL or triglyceride High density lipoproteins < 35 mg/dL or triglyceride levels ≥ 250 mg/dLlevels ≥ 250 mg/dL

• Gestational diabetes or given birth to an infant Gestational diabetes or given birth to an infant weighing > 9 poundsweighing > 9 pounds

• Pre-adm , pre-cath, pre-op , pre-CABG Pre-adm , pre-cath, pre-op , pre-CABG

FBS >100, ppg >140, POC HgA1c >6.0FBS >100, ppg >140, POC HgA1c >6.0

9

Hyperglycemia

SpikePPG

ContinuousA1C

Acute toxicity Chronic toxicity

Tissue lesion

Diabetic complications (Brownlee hypothesis)

Microvascular Macrovascular

Retinopathy Nephropathy Neuropathy PVD MI Stroke

American Diabetes Association. At: http://www.diabetes.org/diabetes-statistics/complications.jsp.Brownlee M. Diabetes mellitus: theory and practice. Elsevier Science Publishing Co., Inc; 1990:279-291.

Ceriello A. Diabetes. 2005;54:1-7.

Hyperglycemia Leads to Complications:Risk Starts with Pre-Diabetes

21% 18% 12% % of pts. with complication at DX 60% ASVD

FBS>126

Ppg>200

New Hyperglycemia

#223 (12%)

Known Diabetes

#495 (26%)

Normo- Glycemia

#1168

Mortality, total 16 3 1.7

Mortality, ICU 31 11 10

Mortality, non-ICU 10 1.7 0.8

LOS 9 5.5 4.5

ICU Admission 29 14 9

D/c Dispo.Home 56 74 84

Transition Care 20 15 10

Nursing Home 8 9 4

RISK OF UNRECOGNIZED HYPERGYCEMIA:Effect of Hyperglycemia on Mortality, LOS,

ICU admission, D/C Disposition

Umpierrez, JCEM 2002;87:978

Metabolic Sydrome, IGT, Diabetes, CV Disease

1. Beginning at 83 mg/dL, rising 2-hr pp glucose levels correlated linearly with CHD mortality

2. Even mild glucose elevations (fbs >110) increase mortality in patients undergoing PCI

3. Almost 70% of patients with first MI have IGT or undiagnosed diabetes

4. In multiple studies stress hyperglycemia in AMI is associated with 3-10 x mortality risk in patients without known diabetes

5. In a group of >31,000 patients without known diabetes but with CV disease (CVD), patients, an 18 mg/dL-higher FPG was associated with a 23% increase in the risk of hospitalization for HF

6. Inc mortality in hosp if admitted wth CVA

Cardiovascular disease and diabetes

Bell DSH. Diabetes Care. 2003;26:2433-41.Centers for Disease Control (CDC). www.cdc.gov.T2DM = type 2 diabetes mellitus

Cardiovascular complications

of T2DM

~65% of deaths are due to CV disease

Coronary heart disease

deaths2- to 4-fold

Stroke risk2- to 4-fold

Heart failure 2- to 5-fold

No A1C threshold is apparentFinnish study by Kuusisto et al;UKPDS epidemiologic analysis; EPIC-Norfolk Study

Impaired glucose tolerance (IGT) and postprandial hyperglycemia are CV risk factorsFunagata Diabetes Study;Honolulu Heart Program; DECODE Study; Rancho Bernardo Study

A1C Predicts Coronary Heart Disease in Type 2 Diabetes

Khaw KT et al. Ann Intern Med. 2004;141:413-420.

3.81.7

6.4

2.1

8.7

3

10.2

7.3

16.7

9.6

28.4

16.2

21.9

15.7

0

5

10

15

20

25

30

<5.0% 5.0%-5.4%

5.5%-5.9%

6.0%-6.4%

6.5%-6.9%

7.0% Knowndiabetes

Men

Women

CH

D e

ven

ts(e

ven

ts/1

00 p

erso

ns)

A1C concentration*

*P<0.001 for linear trend across A1C categories.

High Risk of Cardiovascular Events High Risk of Cardiovascular Events in Type 2 Diabetesin Type 2 Diabetes

Cardiovascular deaths

0

5

10

15

20

25

30

35

40

45

50

7-ye

ar in

cide

nce

of

card

iova

scul

ar e

vent

s (%

)

Myocardial infarction

Stroke - +

No diabetes

Type 2 diabetes

Prior myocardial infarction - + - + - + - + - +

Haffner, NEJM 1998, 229-234

THE PREVALENCE OF CHRONIC ANGINA POSES A SIGNIFICANT BURDEN TO THE US HEALTH CARE SYSTEM

• ~16 million Americans have CHD

• ~9.1 million Americans have angina pectoris

500,000 new cases are reported annually

• Mean angina frequency is ~2 episodes per week> 18 million episodes each

week or ~30 episodes each second

American Heart Association. Heart Disease and Stroke Statistics, 2008 Update. Pepine CJ, et al. Am J Cardiol. 1994;74:226-231.

New Cases of Stable Angina Per Year (Among Americans ≥ 45 Years of Age)

Men TotalIn

cid

enc

e (

# o

f N

ew C

ase

s)

320,000

180,000

500,000

Women

SEVERITY OF ANGINA SYMPTOMS PREDICTS POOR SURVIVAL MORTALITY IN

VA PATIENTS (N=8900) WITH CAD

Mozaffarian D, et al. Am Heart J. 2003;146:1015-1022.

Years

0

0.74

10 1 2 3 4

*p<0.001 for log-ranktest for equality ofsurvivor function

75-10050-7425-49

0-24

Survival According to Physical Limitation Due to Angina (Seattle Angina Questionnaire Score)

Little to no limitation

Greatest limitation: 2.5 fold higher risk of death

Mild limitation: 27% higher risk of death

Moderate limitation: 61% higher risk of death

After adjustment for potential confounders, greater physical limitation due to angina was associated with increased risk of death compared with patients with little or no limitation

Pathophysiology of Diabetic Complications: Implications for Goals of Therapy

I Metabolic DisorderGlucose, insulin hormones, enzymes, metabolites, etc. (i.e., control)

IIIndividual SusceptibilityGenetic/ethnic?Acquired

IIIModulating FactorsHypertension, diet, smoking, etc.

Delayed ComplicationsRetinal, renal neural, CV, cutaneous, etc.

IVEarly

VLate

Point of metabolic“no return”

Epidemiology

1. Hyperglycemia is a continuous

Risk Factor

2. No A1C threshold is apparent

3. Worse >A1C, longer duration DM

Mechanisms

1. Unified Theory of Brownlee

2. Oxidative stress

3. AGE, PKC, Hexosamine,Aldose Reductase

Eg: Macro-albuminuria; Proliferative retinopathy