1. Beginning the Journey with Type 2 Diabetes
James W. Reed, M.D., MACP, FACE
Professor of Medicine, Associate Chair of Medicine
Chief of Endocrinology & Metabolism
Chief of Medicine Service at Grady for MSM

2. Global Projections for the Diabetes Epidemic:
26.5
32.9
24%
14.2
17.5
23%
9.4
14.1
50%
84.5
132.3
57%
1.0
1.3
33%
15.6
22.5
44%
World
2000 = 151 million
2010 = 221 million
Increase 46%

3. Diabetes in the United States
>30% of individuals aged >60 y have diabetes mellitus or impaired fasting glucose
23.6 million have diabetes
Millions of these people are unaware they have diabetes
>1.3 million Americans develop diabetes yearly, >2,800 daily
Harris et al. Diabetes Care. 1998;21: update.

4. Costs of Diabetes (US) 1 in every 7 health care dollars spent
10-15% of Medicare population has diabetes, but 25% of Medicare budget is spent on diabetes
Estimated total costs attributable to diabetes (direct and indirect) ~ $174 billion (2007)
Ranks #1 in direct health care costs of any disease category ~ $174 billion (2007)
Ranks #2 in total health care costs (direct and indirect, diabetes and other) ~ $262 billion (2007)
Slide 5: Costs of Diabetes (US)
Diabetes is responsible for significant healthcare costs in the United States:
1 in every 7 healthcare dollars is spent on patients with diabetes.
Although only 10-15% of the Medicare population has diabetes, as much as 25% of the Medicare budget is devoted to diabetes care.
The total direct and indirect costs attributable to diabetes in 1997 were estimated to be $98 billion.
Diabetes ranks as #1 in direct health care costs, a number estimated to be $91.1 billion in 1995.
Diabetes ranks as #2 in total healthcare costs, a number estimated to be $137.7 billion in 1995.
Songer TJ, Ettaro L. Studies on the cost of diabetes. Centers for Disease Control. Atlanta, GA
Centers for Disease Control and Prevention. Chronic diseases and conditions. Online edition. Atlanta, GA
American Heart Association. Heart and stroke statistical update. Dallas, TX
American Diabetes Association. Diabetes Facts and Figures. March Online Edition.
Songer TJ, Ettaro L. Studies on the cost of diabetes. Centers for Disease Control. Atlanta, GA
Centers for Disease Control and Prevention. Chronic diseases and conditions. Online edition. Atlanta, GA
American Heart Association. Heart and stroke statistical update. Dallas, TX
American Diabetes Association. Diabetes Facts and Figures. March Online edition.

5. Diabetes: The Burden of Disease
In 2007, diabetes-related economic losses were estimated to be:
$174 billion direct health care costs
13.9 million hospital days
30.3 million office visits
120 million work-loss days
88 million disability days
Diabetes Facts and Figures, American Diabetes Association, 2000.

6. Etiology of Type 2 Diabetes: Insulin Resistance and Diminished Insulin Secretion
Genes
Lifestyle and diet
Insulin Resistance
Normal -cell function
Abnormal -cell function
This diagram shows the contributions of insulin resistance and insulin deficiency to the expression of type 2 diabetes. The syndrome of insulin resistance develops over time in individuals who are genetically predisposed. Dietary and lifestyle factors such as obesity or a sedentary existence can also contribute to insulin resistance.
Evidence of insulin resistance is found by examining the in vivo effectiveness of exogenous insulin in stimulating glucose uptake in peripheral tissues and glucose output by the liver. Larger amounts of insulin required to maintain glucose homeostasis indicate greater degrees of insulin resistance.1 When pancreatic -cell function is normal, insulin output increases to compensate for insulin resistance in such tissues as the liver, skeletal muscle, and adipose tissue, and the patient’s glucose tolerance remains within the normal range. However, if -cell function is abnormal or deteriorates, the amounts of insulin secreted by the pancreas are insufficient to compensate for insulin resistance, resulting in hyper-glycemia.
Reference
1. Felig P et al. In: Endocrinology and Metabolism. 3rd ed. McGraw-Hill Inc; 1995.
Compensatory Hyperinsulinemia
Relative insulin deficiency
Hyperglycemia
Normoglycemia
Type 2 diabetes

7. Insulin Resistance: Inherited and Acquired Influences
Overeating
Overweight
Inactivity
Aging
Medications
Illness
Hyperglycemia/
glucose toxicity
Elevated FFAs
Rare Mutations
Insulin receptor
Glucose transporter
Signaling proteins
Common Forms
Largely unidentified
INSULIN RESISTANCE

8. Cardiovascular Disease US Leading Cause of Death (1998)
800
700
600
500
Deaths (thousands)
400
300
200
Despite advances in therapy including increasing use of antiplatelets, lipid-lowering therapy, calcium channel blockers, and beta-blockers, heart disease remains the leading cause of death in the United States. In 1998, of the more than 724,000 deaths attributed to this cause, more than 460,000 were caused by coronary heart disease. Stroke was the third leading cause of death in this year, resulting in more than 158,000 deaths. Stroke is the leading cause of disability.
Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI. May 2000 (National Center for Health Statistics. Preliminary data for National Vital Statistics Report. Vol. 47, no. 25. Hyattsville, MD. 1999).
100
Heart disease
Cancer
Stroke
COPD
Morbidity & Mortality: 2000 Chart Book on Cardiovascular, Lung, and Blood Diseases. NHLBI. May 2000.

9. Prevalence of Diabetic Tissue Damage
at Diagnosis of Type 2 Diabetes
Prevalence
Dagogo-Jack et al. Arch Int Med. 1997;157:

10. UKPDS: Complications at Diagnosis
Tissue Damage Prevalence (%)*
Retinopathy (>1 microaneurysm) 21
Abnormal ECG 18
Other macrovascular complication 9
Absent foot pulses (2) and/or ischemic feet 14
Impaired reflexes and/or decreased vibration sense 7
50% of patients had some form of diabetic complication at time of diagnosis.
*Some patients had more than 1 complication at diagnosis. Adapted from UKPDS. Diabetologia. 1991;34:

11. Duration of follow-up (y) Duration of follow-up (y)
Framingham Study and Joslin Patients
Diabetes Is a CV Risk Factor
Men
Women 60 60 50 50 2x 40 40
4-5x
Mortality rate per 1,000
Mortality rate per 1,000 30 30 20 20 10 10
0-3
4-7
8-11
12-15
16-19
20-23
0-3
4-7
8-11
12-15
16-19
20-23
Duration of follow-up (y)
Duration of follow-up (y)
Diabetes
No Diabetes
Krolewski AS et al. Am J Med. 1991;90(suppl 2A):56S-61S.

12. Methods for Diagnosing Diabetes
FPG 126 mg/dL (after 8-h fast, confirmed)
Casual plasma glucose 200 mg/dL with classic diabetes symptoms (confirmed):
increased urination
increased thirst
unexplained weight loss
OGTT value of  200 mg/dL in the 2-h sample
Don’t use for diagnosis, but still suggestive:
Fingerstick glucose
A1c
ADA. Diabetes Care. 2003;26:S5-S20.

13. Clinical Identification of the Metabolic Syndrome
National Cholesterol Education Program
Clinical Identification of the Metabolic Syndrome
RISK FACTOR DEFINING MEASURES
Abdominal obesity Waist circumference:
Men >40 in (>102 cm)
Women >35 in (>88 cm)
Triglycerides ³150 mg/dL
HDL-C Men <40 mg/dL
HDL-C Women <50 mg/dL
Blood pressure ³130/³85 mm Hg
Fasting glucose ³110 mg/dL
Slide 53: Current Treatment Paradigm
The current treatment paradigm for type 2 diabetes consists of a stepwise approach with diet followed by a single oral agent, a second oral agent, and eventually insulin. Data from NHANES III indicate that the majority of patients with type 2 diabetes are poorly controlled by this approach.
Failure of monotherapy results from the progressive nature of the disease and because a single drug does not address the defects in insulin secretion, hepatic glucose production, and peripheral insulin resistance that characterize type 2 diabetes.
Furthermore, by waiting for failure before changing therapy, glucose toxicity may develop before the therapy is adjusted and impair the treatment response.
Harris MI, Eastman RC, Cowie CC, et al. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 1999;22:
Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, Diabetes Care. 1998;21:
³3 Risk factors comprise the metabolic syndrome. ICD-9 Code 277.7
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA :

14. Aggressive Control of Diabetes:
Goals of Treatment
NORMAL GOAL AMERICAN DIABETES ASSOCIATION HbA1C (%) < 6 < Preprandial plasma glucose (mg/dL) <
Peak postprandial plasma glucose (mg/dL) <140 < 180
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS (AACE) HbA1C (%) < 6  Preprandial plasma glucose (mg/dL) <110 < hour postprandial glucose <140 <140
Target goals for levels of glycemic control have been established by the ADA, the European Diabetes Policy Group (EDPG), and the American Association of Clinical Endocrinologists (AACE).
The ADA recommends a goal of mg/dL for preprandial glucose and <7% for HbA1C.
The EDPG recommends a goal of <110 mg/dL for preprandial glucose and 6.5% for HbA1C.
The AACE recommends a goal of 110 mg/dL for preprandial glucose and 6.5% for HbA1C.
Based on the results from epidemiologic studies, CV risk and overall mortality are decreased in individuals with lower values of HbA1C with no evidence of threshold. Based on these data, the new guidelines advocate more aggressive glycemic control.
American Diabetes Association Clinical Practice Recommendations Diabetes Care. 2001;24(suppl 1):S1-S133.
European Diabetes Policy Group. A desktop guide to type 2 diabetes mellitus. Diabet Med. 1999;16:
American College of Endocrinology Consensus Conference on Guidelines for Glycemic Control White Paper. Washington, DC: AACE, August Available at:
HbA1c is “gold standard” measure of diabetes control over previous 2-3 months
American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S33-S50;
American College of Endocrinology Consensus Conference on Guidelines for Glycemic Control. August 2001, Washington, DC.

15. Lower A1C Reduces Incidence of Complications
DCCT
9  7%
63%
54%
60%
41%*
Kumamoto
9  7%
69%
70% –
UKPDS
8  7%
17-21%
24-33% –
16%*
A1C
Retinopathy
Nephropathy
Neuropathy
Macrovascular disease
Three independent studies: DCCT (type 1), Kumamoto (type 2-lean), UKPDS (type 2-typical) showed significant benefits of similar magnitude by decreasing HbA1c.
In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely.
The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant.
*Not statistically significant.
Diabetes Control and Complications Trial (DCCT) Research Group. N Engl J Med. 1993;329:
Ohkubo Y et al. Diabetes Res Clin Pract. 1995;28:
UK Prospective Diabetes Study Group (UKPDS) 33. Lancet. 1998;352:

16. DECODE Trial: Relative Risk of Death* Shown by Blood Glucose Level
*All causes, adjusted for age, sex, study center
2.4
2.0
Relative Risk of Death*
1.6
1.2
> 199
1.0
< 110
2-h Postprandial Glucose (mg/dL)
>140
< 140
Fasting Plasma Glucose (mg/dL)
Adapted from Decode Study Group. Lancet. 1999;354:

17. Postprandial Glucose Is a Better Predictor of Myocardial Infarction and Death
Glycemic Control (Blood Glucose Level, mg/dL)
Good Borderline Poor P Value
Fasting 80– –139 >140 —
MI per 1, NS
Death per 1, NS
Postprandial 80– –179 >180 —
MI per 1, <.05
Death per 1, <.05
Hanefeld and colleagues showed that postprandial hyperglycemia is a better predictor of myocardial infarction and death than fasting glucose in patients with type 2 diabetes.
These data show the risk of myocardial infarction or death, based on fasting or postprandial blood glucose as the predictor, segregated across good, borderline, and poor control. While the postprandial values provided statistically significant prognostic information, the fasting levels did not.
Hanefeld M et al. Diabetologia. 1996;39:

18. Effects of Risk Factors on CVD Mortality in Type 2 Diabetes - MRFIT
140
120
100 80 60 40 20
Nondiabetic
Diabetic
CVD death
rate* per
10,000
person-years
None
One
Two
Three
Number of risk factors
*Age adjusted
Adapted from Stamler J et al. Diabetes Care. 1993;16:

19. Atherosclerosis Timeline
Foam
cells
Fatty streak
Intermediate lesion
Complicated lesion/rupture
Fibrous plaque
Atheroma
Endothelial dysfunction
Atherosclerosis timeline
Content points:
• The pathological effects of atherosclerosis occur over decades. A subtle injury to the endothelium initiates the atherosclerotic process.3 Injury of the vascular wall and endothelium underlie many stages in atherosclerosis progression from onset through formation of advanced lesions and clinical events.4
• Foam cells infiltrate the vessel and progress to formation of a fatty streak. Small pools of extracellular lipid form within the smooth muscle cell layers, disrupting the intimal lining of the vessel. The formation of atheroma and fibrous plaque, a pearly white area within the artery, disturbs the arterial wall.
• The atheroma, or plaque, is composed of lipid, cell debris, smooth muscle cells and collagen (or calcium, in older persons). This type of advanced lesion can be found beginning in the fourth decade of life. Once the plaque becomes fibrous, the danger of rupture increases.
• The clinically important complication of atheroma usually involves thrombosis. Most coronary thromboses result from rupture of the protective fibrous cap, which permits contact between the blood and the highly thrombogenic material in the lipid core of the lesion.
• Stenoses seldom cause acute MI. Indeed, sizable atheromas may remain silent for decades or produce stable angina due to increased demand.
From First Decade
From Third Decade
From Fourth Decade
Thrombosis
Hematoma
Smooth Muscle & Collagen
Growth Mainly by Lipid Accumulation
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 10A):23S-27S.

20. UKPDS: Metformin Study Results in Overweight Patients
Conventional
A1C = 7.4% A1C = 8.0%
Risk* P value Risk* P value
32% 7% NS
Any diabetes-related
end point
42% 20% NS
Diabetes-related
deaths
39% 21% NS
Myocardial infarction
41% NS 14% NS
Stroke
Microvascular disease
29% NS 16% NS
*Compared with conventional therapy. .
UKPDS Group. Lancet. 1998;352:

21. Thiazolidinediones in
Diabetes Therapy
Mechanism of action reverses underlying etiology
TZDs improve insulin sensitivity
Glucose control achieved without hypoglycemia
TZD monotherapy or metformin combination (no increase in insulin)
Possible secondary benefits include:
Preservation of pancreatic b-cell function
May help reduce progression of disease
Protective cardiovascular effects
Improve dyslipidemia( ↑HDL,↓TG, ↓LDL density)
↓Renal microalbumin excretion
↓VSMC proliferation and migration in arterial wall
Enhance thrombolytic mechanisms

22. MICRO-HOPE: Primary Outcomes
Nonfatal MI
Total mortality
Stroke
CV Death -5
-10 %
-15
-20
-25
22%‡
24%†
-30
33%§
-35
*P<.0001
‡P<.01
§P<.0074
†P<.004
-40
37%*
The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet. 2000;355:

23. HOPE and MICRO-HOPE: Event Reductions for Primary End Points and Total Mortality
25%
Total mortality
16%
33%
Stroke
32%
22% MI
20%
37%
CV death
26% 5 10 15 20 25 30 35 40
Percent
Diabetic Overall
The HOPE Study Investigators. Lancet. 2000;355:

24. The Deadly Quartet Insulin Resistance Type 2 Diabetes
Hypercoagulability
Insulin Resistance
Dyslipidemia
Hypertension

25. Recognizing the Insulin-Resistant Patient
Insulin resistance is associated with:
Abdominal obesity
Glucose intolerance
First-degree relative with type 2 diabetes
Absent nocturnal drop in BP
Salt sensitivity
History of gestational diabetes
Dyslipidemia
Hypertension
Increased PAI-1/ Platelets
Acanthosis nigricans

26. Nutrition Therapy, Exercise, Lifestyle Changes
decrease fat content and total calories
decrease saturated fat
decrease salt for hypertension
healthy diet
weight reduction in obese patients
Exercise
increase energy expenditure with moderate-intensity exercise
Lifestyle changes to reduce cardiovascular risk factors (eg, smoking cessation)
Training in self-management and SMBG
©1997 PPS

27. Sulfonylureas: Mechanism of Action
1 Intestine: glucose absorption
2 Muscle and adipose tissue: glucose uptake
Insulin resistance
Blood glucose
4 Liver: hepatic glucose output
Insulin resistance
3 Pancreas: insulin secretion Sulfonylureas insulin secretion
DeFronzo RA. Diabetes. 1988;37:
Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:
©1997 PPS

28. Meglitinides: Mechanism of Action
1 Intestine: glucose absorption
2 Muscle and adipose tissue: glucose uptake
Insulin resistance
Blood glucose
4 Liver: hepatic glucose output
Insulin resistance
3 Pancreas: insulin secretion
Meglitinides
Insulin secretion
Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:
©1998 PPS

29. Metformin: Mechanism of Action
1 Intestine: glucose absorption
2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization
Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
Metformin HGO
Insulin resistance
3 Pancreas: insulin secretion
©1997 PPS
DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:

30. a-Glucosidase Inhibitors: Mechanism of Action
1 Intestine: glucose absorption Acarbose glucose absorption secondary to digestion of carbohydrate
2 Muscle and adipose tissue: glucose uptake
Insulin resistance
Blood glucose
4 Liver: hepatic glucose output
Insulin resistance
3 Pancreas: insulin secretion
Amatruda JM. In: Diabetes Mellitus
©1997 PPS