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Type 2 Diabetes Update Prevention and Treatment
Bruce W. Bode, MD, FACE Atlanta Diabetes
Associates Atlanta, Georgia
3
Prevalence of Diabetes in the US
Diagnosed Type 1 Diabetes0.5 1.0
Million
Diagnosed Type 2 Diabetes10.3 Million
Undiagnosed Diabetes5.4 Million
American Diabetes Association. Facts and Figures.
Available at http//www.diabetes.org/ada/facts.as
p. Accessed January 18, 2000.
4
Goals of Intensive Diabetes Management

• Near-normal glycemia
• HbA1c less than 6.5 to 7.0
• Avoid short-term crisis
• Hypoglycemia
• Hyperglycemia
• DKA
• Minimize long-term complications
• Improve Quality of Life

ADA Clinical Practice Recommendations. 2001.
5
Causes of Death in People With Diabetes
50
40
of Deaths
30
20
10
0
Ischemic Heart Disease
Other Heart Disease
Diabetes
Cancer
Stroke
Infection
Other
Geiss LS, et al. In Diabetes in America, 2nd ed.
1995. Bethesda, MD National Institutes of
Health 1995chap 11.
5
6
Natural History of Type 2 Diabetes
Obesity IGT Diabetes
Uncontrolled
Hyperglycemia
Post-Meal Glucose
Plasma Glucose
Fasting Glucose
120 (mg/dL)
Relative ?-Cell Function
Insulin Resistance
100 ()
Insulin Secretion
-20
-10
0
10
20
30
Years of Diabetes
IGT impaired glucose tolerance.
Adapted from International Diabetes Center (IDC),
Minneapolis, Minnesota.
7
Insulin Resistance An Underlying Cause of Type 2
Diabetes
Reaven GM. Physiol Rev. 199575473-486 Clauser,
et al. Horm Res. 1992385-12.
8

• Recognition of the Metabolic Syndrome and Insulin
  Resistance
• The metabolic syndrome is defined by the presence
  of gt3 of the following risk factors
• Abdominal obesity
• Atherogenic dyslipidemia
• Small LDL particle size
• Low HDL cholesterol
• Elevated triglycerides
• Increased blood pressure
• Elevated fasting blood glucose

NCEP ATP III. JAMA. 2001285(19)2486-95.
9
Diagnostic Criteria Associated with Glucose
Abnormalities
FPG
2-Hour PG on OGTT
Diabetes Mellitus
Diabetes Mellitus
126 mg/dL
7.0 mmol/L
200 mg/dL
11.1
mmol/L
Impaired FastingGlucose
Impaired Glucose Tolerance
110 mg/dL
6.1 mmol/L
140 mg/dL
7.8
mmol/L
Normal
Normal
Adapted from The Expert Committee on the
Diagnosis and Classification of Diabetes
Mellitus. Diabetes Care. 200124(Suppl 1)S5-S20.
10
Type 2 Diabetes Two Principal Defects
Reaven GM. Physiol Rev. 199575473-486 Reaven
GM. Diabetes/Metabol Rev. 19939(Suppl
1)5S-12S Polonsky KS. Exp Clin Endocrinol
Diabetes. 1999107 Suppl 4S124-S127.
11
Role of Free Fatty Acids in Hyperglycemia
Adipose tissue insulin resistance
ADIPOSE TISSUE
MUSCLE
? Lipolysis
LIVER
Muscle insulin resistance
? FFA mobilization
Liver insulin resistance
? FFA oxidation
? FFA oxidation
? Gluconeogenesis
? Glucose utilization
Hyperglycemia
Boden G. Proc Assoc Am Physicians.
1999111241-248.
12
Insulin Resistance and ?-Cell Dysfunction Produce
Hyperglycemia in Type 2 Diabetes
?-Cell Dysfunction
Insulin Resistance
Increased Lipolysis
Pancreas
Elevated Plasma FFA
Liver
-

Islet ?-Cell DegranulationReduced Insulin
Content
Muscle
Adipose Tissue
Increased Glucose Output
Reduced Plasma Insulin
Decreased Glucose Transport Activity
(expression) of GLUT4
Hyperglycemia
Courtesy of S. Smith, GlaxoSmithKline
13
HbA1c in the UKPDS
14
Intensive Treatments and HbA1c
UKPDS Metformin Substudy
Conventional
9
Insulin
Chlorpropamide
Glibenclamide (glyburide)
8
Metformin
ADA action
Median HbA1c ()
7
ADA goal
6
Upper limit of normal range (6.2)
0
10
3
6
9
0
Time from randomization (y)
Adapted from UK Prospective Diabetes Study
(UKPDS) Group. Lancet. 1998352854-865.
15
UKPDS b-Cell Function for the Patients
Remaining on Diet for 6 Years
b-Cell Function ( b)
N376
Years After Diagnosis
Adapted from UKPDS Group. Diabetes. 1995
441249-1258.
16
UKPDS ?-Cell Function Over Time Obese
Subgroup
100
Sulfonylurea
75
b-Cell Function (?)
Metformin
50
Diet
25
0
1
2
3
4
5
6
Years
UKPDS 16, Diabetes 1995 4412491258
17
Multiple factors may drive progressive decline of
b-cell function
Hyperglycaemia (glucose toxicity)
Insulin resistance
b-cell (genetic background)
Protein glycation
lipotoxicity elevated FFA,TG
Amyloid deposition
18
Lowering HbA1C Reduces Risk of Complications
United Kingdom Prospective Diabetes Study (UKPDS)
0 -10 -20 -30 -40 -50
Any diabetes-related endpoint Microvascular
endpoint MI Retinopathy Albuminuria at 12 years
-12
-16
p0.029
p0.052
-21
Reduction in risk ()
-25
p0.015
p0.0099
-34
p0.000054
Percent risk reduction per 0.9 decrease in
HbA1C UKPDS. Lancet. 1998352837-853.
19
UKPDS Benefits of Glycemic Control in Type 2
Diabetes
Risk reduction over 10 years Any
diabetes-related endpoint 12 P
0.029 Microvascular endpoints 25 P
0.0099 Myocardial infarction 16 P
0.052 Cataract extraction 24 P
0.046 Retinopathy at 12 years 21 P
0.015 Microalbuminuria at 12 years 33 P lt
0.001
UKPDS 33. Lancet. 1998352837-853.

20
Metformin Prevents Heart Attacks and Reduces
Deaths in Type 2 Diabetes
Heart Attacks
Coronary Deaths
P0.01
P0.02
39?Reduction
50?Reduction
Incidence(per 1,000 patient years)
Conventional Metformin Therapy
Conventioal Metformin Therapy
21
Diabetes Prevention Program

• 3234 obese patients with IGT
• BMI average 34 A1C 5.9, 55 Caucasion
• 4 year study to compare diet and exercise to
  metformin, troglitazone or control
• Troglitazone stopped at 8 months
• Study ended after 3 years

22
Diabetes Prevention Program

• 58 prevention with diet (low fat) and exercise
  (2.5 hours per week)
• 31 prevention with metformin (more effective if
  lt 60 years old and obese)
• Troglitazone patients equal to metformin group at
  three years and equal to the diet and exercise
  group at 8 months.

23
Preventing Diabetes after GDM
The Strategy
Insulin Secretion
Resistant
Sensitive
Insulin Sensitivity
24
Troglitazone In the Prevention Of Diabetes
TRIPOD A Test of Workload Reduction for B-cells
Azen et al Contr Clin Trials, 1998
25
Preventing Diabetes The TRIPOD Study
60
40
RR0.44
People with Diabetes
20
0
0
10
20
30
40
50
60
Months on Study
26
TRIPOD Metabolic Changes during First Three
Months and Long-Term Risk of Diabetes
Data from 108 women randomized to troglitazone
27
Randomization
Placebo
Troglitazone
DM Rate
12.3/yr
Small Change
Large Change
in S
in S
I
I
DM Rate
9.8/yr
Small Fall in
Large Fall in
Insulin Levels
Insulin Levels
DM Rate
DM Rate
0/yr
5.8/yr
28
Early Changes in Insulin Sensitivity and Insulin
Secretion and Subsequent Diabetes Rates
Troglitazone Group
DM Rate 9.8 per year
DM Rate 5.8 per year
DM Rate 0 per year
29
TRIPOD Off-Trial Follow-up Study
On Trial
Off Trial
40
Diabetes
30
Fraction with Diabetes
20
10
0
Observed2.4
0
10
20
30
40
Months after Randomization
30
TRIPOD Long Term Stability of Glucose Tolerance
Women without Diabetes during Troglitazone
Treatment
50 women randomized to troglitazone completed
the trial without diabetes. Data are from the 41
who returned for post-trial testing.
31
TRIPOD Conclusion
Reducing secretory demands placed on pancreatic
B-cells by chronic insulin resistance can delay
or prevent the onset of type 2 diabetes.
B-cell rest B-cell protection
32
Management of Type 2 DMStep Therapy

• Diet
• Exercise
• Sulfonylurea or Metformin
• Add Alternate Agent
• Add hs NPH vs TZD
• Switch to Mixed Insulin bid
• Switch to Multiple Dose Insulin

Prone to Failure from Negative Reinforcement Missc
heduling, Mismanagement
33
Management of Type 2 DM Stumble Therapy

• WAG Diet
• Golf Cart Exercise
• Sample of the Week Medication
• Interrupted
• Not Combined
• Poor Understanding of Goals
• Poor Monitoring

HbA1c gt8 (If Seen)
34
Consider A New Treatment Paradigm

• Treatment designed to correct the dual
  impairments
• Vigorous effort to meet glycemic targets
• Simultaneous rather than sequential therapy
• Combination therapy from the outset
• Early step-wise titrations to meet glycemic
  targets

35
ACE / AACE Targets for Glycemic Control

• HbA1c lt 6.5
• Fasting/preprandial glucose lt 110 mg/dL
• Postprandial glucose lt 140 mg/dL

ACE / AACE Consensus Conference, Washington DC
August 2001
36
Goals in Management of Type 2 Diabetes

• Fasting BG lt 110 mg/dL
• Post-meal lt 140 mg/dL
• HbA1c lt 6.5
• Blood Pressure lt 130/80
• LDL lt 100 mg/dl
• HDL gt 45 mg/dl

37
Sites of Action by Therapeutic Options Presently
Available to Treat Type 2 Diabetes
MUSCLE
ADIPOSE TISSUE
LIVER
PANCREAS
GLUCOSE PRODUCTION Biguanides Thiazolidinediones
PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Big
uanides)
INSULIN Secretion Sulfonylureas Meglitinides Insul
in
INTESTINE
GLUCOSE ABSORPTION
alpha-glucosidase inhibitors
Sonnenberg and Kotchen. Curr Opin Nephrol
Hypertens 19987(5)5515
38
Oral Therapy for Type 2 Diabetes Target Sites of
Action
SulfonylureasRepaglinide
Pancreas
Gut
Adipose tissue
? Insulin secretion
? Glucose uptake ? FFA output
Acarbose Miglitol
? Glucose absorption
? Hyperglycemia
Rosiglitazone Pioglitazone
Liver
Muscle
Metformin Rosiglitazone Pioglitazone
Rosiglitazone Pioglitazone Metformin
?Glucose uptake
? Hepatic glucose output
Avandia (rosiglitazone maleate) PI.
GlaxoSmithKline, February 2001. Actos
(pioglitazone HCl) PI. Takeda Pharmaceuticals,
May 2001. Prandin (repaglinide) PI. Novo
Nordisk, August 2000. Precose (acarbose) PI.
Bayer Corporation, October 1999. GlysetTM
(miglitol tablets) PI. Pharmacia/Upjohn,
September 1999. Glucophage (metformin HCl) PI.
Bristol-Myers Squibb, June 2001.
39
Visceral Fat Distribution Normal versus Type 2
Diabetes
Normal
Type 2 Diabetes
Courtesy of Wilfred Y. Fujimoto, MD.
40
The Metabolic SyndromeA Network of Atherogenic
Factors

• Type 2 diabetes and glycemic disorders
• Dyslipidemia
• - Low HDL
• - Small, dense LDL particles
• Hypertriglyceridemia
• Hypertension
• Impaired thrombolysis
• - ? PAI-1
• Endothelial dysfunction/inflammation
• - ? CRP, MMP-9
• Microalbuminuria

Insulin Resistance ? Free Fatty Acids
VisceralObesity
Atherosclerosis
Brunzell J, Hokanson J. Diabetes Care.
199922(Suppl 3)C10-3. McFarlane S, et al. J
Clin Endocrinol Metab. 200186(2)713-8. Frohlich
M, et al. Diabetes Care. 2000 Dec23(12)1835-9. K
uusisto J, et al. Circulation. 199591831-7. Paru
lkar AA, et al. Ann Intern Med.
200113461-71. Hseuh WA, et al. Diabetes Care.
2001 Feb24(2)392-7. Lebovitz H. Clin Chem.
199945(8B)1339-45.
41
Thiazolidinediones Mode of Action
Peroxisome Proliferator-Activated Receptors

• PPARg
• Affects glucose, lipid and protein metabolism
• PPARa
• Affects lipoprotein metabolism
  (some TZDs)

Saltiel Olefsky. Diabetes 19964516619
42
Thiazolidinediones Mechanism of Insulin
Sensitization
TZD
INSULIN
RECEPTOR
Protein
PPAR
RXR
signaling
downstream events
TZD
RNA
PPAR
TF
RXR
DNA
TZD - thiazolidinedione
PPAR RXR - nuclear receptors
TF - transcription factors
Saltiel Olefsky. Diabetes 19964516619
43
ThiazolidinedionesRationale for Type 2 Diabetes
Therapy

• Proven characteristics
• Target insulin resistance, a core defect
• Improve glycemic control
• Do not cause hypoglycemia
• Improve lipid profile (pioglitazone and
  troglitazone)
• Potential benefits
• Preservation of pancreatic b-cell function
• Prevention of progression from impaired glucose
  tolerance to type 2 diabetes
• Improvement in cardiovascular outcomes

Saltiel Olefsky. Diabetes 19964516619 Sonnenb
erg and Kotchen. Curr Opin Nephrol Hypertens
19987(5)5515
44
Changes in HbA1C at Endpoint in All Treated
Patients
ACTOS (pioglitazone HCl) U.S. Clinical Trials

Daily dose ofACTOS
D HbA1Cat week 26( points)





Change from Baseline
Difference from Placebo
LOCF
p 0.05
Takeda Pharmaceuticals America, Data on file
Study 001
45
Change in Lipid Profile at Endpoint ACTOS Added
to Sulfonylurea
D from baseline at 16 weeks
(n 189)

()

HDL cholesterol
LDL cholesterol
Triglycerides
Total cholesterol
Baseline (mg/dL)
258.6
126.5
123.7
41.8
42.9
214.4
211.5
259.5
LOCF p 0.05 vs. placebo
Takeda Pharmaceuticals America, Data on file
Study 010
46
Mean Triglycerides Over Time
350
Gly (n35)
RSG 8 mg/day (n45)
300
250
200
Mean triglycerides (mg/dL)
150
100
50
0
0
12
28
40
52
64
76
88
100
Treatment week
Error bars SE Given in divided doses Study
080, 100-week completer analysis Data on file
GlaxoSmithKline
47
Differential Effects on Insulin Sensitivity
Assessed by Glucose Disposal, Plasma Insulin and
FFA



6
-21
44
Glucose disposal rate
(uU/mL)
20
Fasting plasma insulin
(mg/kg/min)
MET
TRO
MET
TRO
Baseline

16 weeks
(meq/L)
Fasting plasma FFA
-24
9
MET, metformin TRO, troglitazone p0.04
p0.01 Kim DD, et al. Diabetes.
200049Abstract 459.
MET
TRO
48
Differential Effects on Endogenous Glucose
Production
MET
TRO
0
pns
-5
-10
Change in endogenous glucose production ()
-15
p0.001
-20
p0.04
-25
MET, metformin TRO, troglitazone Inzucchi SE,
et al. N Engl J Med. 1998338867-872.
49
Incidence of Edema
ACTOS (pioglitazone HCl) Summary of Adverse
Events
U.S. Placebo-controlled Studies
()
28/373
10/168
4/160
4/187
58/379
13/187
3/259
29/606
Monotherapy
Combination withsulfonylurea
Combination withmetformin
Combination withinsulin
2 patients from combination therapy trials and
0 from the monotherapy trials discontinued due to
edema
Pioglitazone HCl Package Insert July, 1999
50
Patient Case 1

• Patient JM DOB 11/30/1943
• Problem List
• 1. Diabetes Mellitus, onset 1981,age 38
• a. Insulin therapy, 10/88 through 3/92, A1c 9.0
• C-peptide of 5.1
• b. Metformin and Glyburide therapy. A1c 7.7-
  8.9
• c. Troglitazone therapy 400 mg/day, 5/97 through
  3/99 A1c 8.9 to 7.1 then to 8.1
• d. Pioglitazone added 12/99
• A1c 8.1 to 6.3-6.5 range.

51
Case 1 Contd

• 2. Hypertriglyceridemia
• Simvastatin therapy with TG of 402 mg/dL
• Pioglitazone added
• TG levels fell to 140 mg/dL

52
Patient Case 2

• Patient CM DOB 11/17/1935
• Problem List
• 1. Type 2 Diabetes, Onset 1993, age 59
• a. Troglitazone added to Metformin and
  Repaglinide,
• 3/98 A1c 9.6 to 8.1
• b. Pioglitazone 45 mg added 1/26/00, A1c
  8.1 to 7.3, avg glucose 121 mg/dL
• TG decreased from 206 mg/dL to 118
  mg/dL Tchol 164 mg/dL to 130 mg/dL, LDL 82
  mg/dL to 58 mg/dL, HDL 41 to 46.
• 2. CHD status post PTCA 1989, 1999.

53
Patient Case 3

• Patient EM DOB 9/27/1932
• 1. Type 2 DM, Onset 1995, age 63
• Insulin therapy since onset, post 15 lbs wt loss
  to 185 lbs
• Height 71 inches
• Glucose well controlled on NPH and Regular bid
  until 5/99,
• A1c 8.7
• Changed to NPH at am and hs with pre-meal
  Lispro.
• A1c to 7.0 on 54 - 81 units/day.
  Weight 229 pounds
• Desires insulin pump therapy
• C-peptide 3.7

54
Patient Case 3 Contd

• Changed to Pioglitazone 30 mg/day,
• Glimepiride 4 mg/d, off insulin.
• A1c down 6.2.
• TG decreased from 546 to 182 to 79 mg/dL.
• LDL 191 to 132 (Atorvastatin 10 mg/day).

55
Approach to Combination Oral Therapy
56
Insulin Therapy in Type 2 Diabetes Indications

• Significant hyperglycemia at presentation
• Hyperglycemia on maximal doses of oral agents
• Decompensation
• Acute injury, stress, infection, myocardial
  ischemia
• Severe hyperglycemia with ketonemia and/or
  ketonuria
• Uncontrolled weight loss
• Use of diabetogenic medications (eg,
  corticosteroids)
• Surgery
• Pregnancy
• Renal or hepatic disease

57

• Mimicking Nature
• The Basal/Bolus Insulin Concept

6-16
58
The Basal/Bolus Insulin Concept

• Basal insulin
• Suppresses glucose production between meals and
  overnight
• 40 to 50 of daily needs
• Bolus insulin (mealtime)
• Limits hyperglycemia after meals
• Immediate rise and sharp peak at 1 hour
• 10 to 20 of total daily insulin requirement at
  each meal

59
MIMICKING NATURE WITH INSULIN THERAPY

• Over time,
• most patients will need
• both basal and mealtime insulin
• to control glucose

6-19
60
Starting With Basal Insulin Advantages

• 1 injection with no mixing
• Insulin pens for increased acceptance
• Slow, safe, and simple titration
• Low dosage
• Effective improvement in glycemic control
• Limited weight gain

6-37
61
Treat to Target Study Glargine vs NPH Added to
Oral Therapy of Type 2 Diabetes

• Type 2 DM on 1 or 2 oral agents (SU, MET, TZD)
• Age 30 to 70
• BMI 26 to 40
• A1C 7.5 to 10 and FPG gt 140 mg/dL
• Anti GAD negative
• Willing to enter a 24 week randomized, open
  labeled study

Riddle et al, Diabetes June 2002, Abstract 457-p
62
Treat to Target Study Glargine vs NPH Added to
Oral Therapy of Type 2 Diabetes

• Add 10 units Basal insulin at bedtime
  (NPH or Glargine)
• Continue current oral agents
• Titrate insulin weekly to fasting BG lt 100 mg/dL
• - if 100-120 mg/dL, increase 2 units
• - if 120-140 mg/dL, increase 4 units
• - if 140-160 mg/dL, increase 6 units
• - if 160-180 mg/dL, increase 8 units

Riddle et al, Diabetes June 2002, Abstract 457-p
63
Treat to Target Study A1C Decrease
Riddle et al, Diabetes June 2002, Abstract 457-p
64
Treat to Target Study Patients in Target (A1C lt
7)
Riddle et al, Diabetes June 2002, Abstract 457-p
65
Treat to Target Study Glargine vs NPH Added to
Oral Therapy of Type 2 Diabetes

• Nocturnal Hypoglycemia reduced by 40 in
  the Glargine group (532 events)
  vs NPH group (886 events)

Riddle et al, Diabetes June 2002, Abstract 457-p
66
Advancing Basal/Bolus Insulin

• Indicated when FBG acceptable but
• HbA1c gt 7 or gt 6.5
• and/or
• SMBG before dinner gt 140 mg/dL
• Insulin options
• To glargine or NPH, add mealtime aspart / lispro
• To suppertime 70/30, add morning 70/30
• Consider insulin pump therapy
• Oral agent options
• Usually stop sulfonylurea
• Continue metformin for weight control
• Continue glitazone for glycemic stability?

67
Insulin Monotherapy vs Combination

• 88 Type 2 patients on insulin monotherapy
• Baseline A1C 8.7
• Randomized for 4 months to
• Monotherapy with titration to A1C 5.6
• Metformin 1000 mg BID (no titration)
• Troglitazone 600 mg per day (no titration)

Strowig et al, Diabetes Care 25, 10, October 2002
68
Insulin Monotherapy vs Combination

• Baseline A1C 8.7
• Randomized for 4 months to
• Monotherapy A1C 7.0 ( 55 units/day 0.5
  kg)
• Metformin A1C 7.1 (- 1.4 units/day 4.4
  kg)
• Troglitazone A1C 6.4 (-12.8 units/day 4.4
  kg)

Strowig et al, Diabetes Care 25, 10, October 2002
69
Multiple Daily Injections

• Starting dose 0.2 x wgt. in lbs.
• Wgt. 180 lbs which 36 units
• Bolus dose (lispro/aspart) 20 of starting dose
  at each meal, which 7 units ac (tid)
• Basal dose (glargine) 40 of starting dose at
  HS, which 14 units at HS
• Correction bolus (BG - 100)/ SF, where
  SF 1500/total daily dose 1500/36 40

70
Correction Bolus Formula
Current BG - Ideal BG Glucose Correction factor

• Example
• Current BG 220 mg/dl
• Ideal BG 100 mg/dl
• Glucose Correction Factor 40 mg/dl

220 - 100 40
3.0u
71
Strategies to Improve Glycemic Control Type 2
Diabetes

• Monitor glycemic targets Fasting and
  postprandial glucose, HbA1c
• Self-monitoring of blood glucose is essential
• Nutrition and activity are cornerstones of
  therapy
• Combinations of pharmacologic agents are often
  necessary to achieve glycemic targets

72
Conclusion

• Intensive therapy is
• the best way to treat
• patients with diabetes