Present Therapies of Type 2 Diabetes Mellitus: ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005

Present Therapies of Type 2 Diabetes Mellitus
ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005
Edward S. Horton, MD Professor of Medicine Harvard Medical School Director of Clinical Research Joslin Diabetes Center
2005. American College of Physicians. All Rights Reserved.
MTP 057
Disclosure of Relationships with Commercial Companies Edward S. Horton, MD, FACP
Research Grants/Contracts:Takeda, Lilly, MannKind, Sankyo Honoraria: Merck, Pfizer, Novartis, Takeda, Novo Nordisk Consultantship: Novartis
Main Topics for Discussion

The Diabetes Epidemic The Role of Genes vs. Environment: Obesity, Metabolic Syndrome and Lifestyle Changes The Pathogenesis/Pathophysiology of DM2 and its Complications Strategies for Prevention Drugs for Treatment: Old and New The Global Approach to Treatment of DM2 and CVD Risk Factors The Need to Treat to Target
Global Projections for the Diabetes Epidemic: 2003-2025

NA EUR
23.0 M 36.2 M 57.0%
48.4 M 58.6 M 21%
EMME
WP SEA
19.2 M 39.4 M 105%

AFR
39.3 M 81.6 M 108%
43.0 M 75.8 M 79%
World 2003 = 194 M 2025 = 333 M 72%
SACA
14.2 M 26.2 M 85%
7.1M 15.0 M 111%
2003 2025
M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 2nd Edition: IDF 2003. 2005. American College of Physicians. All Rights Reserved.
The Dual Epidemic: Obesity and Diabetes

65% of adult Americans are overweight (BMI >25) and 21% are obese (BMI >30). 24% have the Metabolic Syndrome. There are now an estimated 18 million people with DM in the USA and even more with IGT. The lifetime risk of developing DM for people born in 2000 is 33% for men and 39% for women. For Hispanic women it is 50%. In this population CVD is the major cause of mortality.
The Prevalence of Overweight and Diabetes over 10 Years

25% increase
8.0%
60.0% 56.4%
49% increase
7.3% 7.0% 6.0% 5.0% 4.9%
50.0% 45.0% 40.0%
4.0% 3.0% 2.0%
30.0%
1.0%
1991
2000
1990
2000
Overweight BMI >25 Kg/m2
Diabetes & Gestational Diabetes
Mokdad et al. Diabetes Care. 2000; 23(9):1278-83. Mokdad et al. JAMA. 2000;286(10):1195-200. 2005. American College of Physicians. All Rights Reserved.
WHAT IS DRIVING THE DUAL EPIDEMIC?
CHANGES IN OUR LIFESTYLE!

es di et et ababes Toi D
R. Heine MD
Metabolic Syndrome ?
The Role of Genes vs. the Environment
The Insulin Resistance Syndrome

Obesity (esp. Abdominal Obesity) Physical Aging Inactivity
Insulin Resistance
Genetic Variation In CVD Risk Factor Regulation
Atherogenic Dyslipidemia
Proinflammatory State
ProElevated thrombotic Blood Pressure Hyperglycemia Modified from S. Grundy MD State

Waist Obesity Circumference (esp. Abdominal Men: > 102 cm (40 in) Obesity) Women: > 88 cm (35 in) Atherogenic ProDyslipidemia inflammatory TG> 150 mg/dL Genetic Variation State In CVD Risk Factor
Metabolic Syndrome ATP III (3 of 5)
HDL-C < 40 mg/dL (M) < 50 mg/dL (F)

Elevated BP
Regulation
BP > 130/85 mmHg
Fasting Glucose >110 mg/dL *
Insulin Resistance
Prothrombotic State
Prevalence of the Metabolic Syndrome Among US Adults Using the ATP III Criteria
National Health and Nutrition Examination Survey III, 1988-1994

50 45 40 35 30 25 20 15 10 5 0 20-29 Men Women
30-39
40-49
50-59
60-69
>70
Age-Adjusted Prevalence is 23.7% n= 8814
Ford et al. JAMA 2002;278:356-359
The Metabolic Syndrome in People with IGT or Diabetes

33% of people 50 yrs. and older with IGT have MS compared to 35-40% in the general population (NHANES III) (Alexander CM et al Diabetes 2003; 52:1210-1214) Only limited data on prevalence of MS in DM2 (approximately 60-65% in Type 2 DM) The increased risk of CVD in IGT and DM2 is well established, but the role of hyperglycemia vs. other CVD risk factors is not well understood. How much does MS contribute? No prospective studies of the development of MS in people with IGT or DM2
DIABETES AND CARDIOVASCULAR DISEASE
IGT Progressively Increases Risk of CHD Mortality: Paris Prospective Study (10-year follow-up)
5 4 CHD Mortality (incidence/1,000) 3 2 1 0 (6055) (690) (158) (135)
G <140 mg/dL
IGT
G 200 mg/dL (newly diagnosed diabetes)
Known Diabetes
P < 0.001
Eschwege E et al. Horm Metab Res. 1995;17(suppl):41-46. 2005. American College of Physicians. All Rights Reserved.
DECODE: Mortality Rate Increases With Increasing 2-Hour Glucose

2 0
(325/2766) (63/432) 15 (146/909) 16
Mortality (%)
1 5
(1172/18,252) 6
12
1 0
5 Fasting glucose: 2-h glucose: (mmol/L) 0
<6.1 <7.8
<7.0 (Not DM) 7.811.0 (IGT)
<7.0 (Not DM) 11.1 (DM)
7.0 (DM) 11.1 (DM)
DECODE = Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe. Adapted from DECODE Study Group. Lancet. 1999;354:617-621. 2005. American College of Physicians. All Rights Reserved.
Seven-Year Incidence of Fatal / Nonfatal MI in Finland

No Diabetes (n = 1373) Diabetes (n = 1059) 45% P < 0.001 P < 0.001
50 45 40 35 7-Year 30 Incidence 25 of MI (%) 20 15 10 5 0
19%
20%
4% No previous MI* Previous MI No previous MI* Previous MI
*At baseline. Haffner SM et al. N Engl J Med. 1998;339:229-234. 2005. American College of Physicians. All Rights Reserved.
Glycemia in Relation to Microvascular Disease and MI

80 MI Microvascular disease
Incidence per 1,000 patient-years
60
40
20
0 5
6 7 8 9 10 11 Updated mean HbA (%)

1 C
UKPDS 35. BMJ 2000;321:40512 2005. American College of Physicians. All Rights Reserved.
Endothelial Dysfunction is an Early Abnormality in Obesity and Pre-diabetes
Leg Blood Flow Changes During Methacholine Infusion

300
% change in leg blood flow above baseline
250
200
BMI <28 BMI >28 Type 2 diabetes
150
100
50
0 2.5 5 7.5 10 12.5
Methacholine chloride infusion rate ( g/min)

Modified from Steinberg H J Clin Invest 1996;97:2601-2610 2005. American College of Physicians. All Rights Reserved.
Flow Mediated Dilation Brachial Artery

16
% Increase Over Baseline
13.7* 12 10.5
9.8 8.4
Controls
Relatives
IGT
Diabetes
*P <0.001 Controls vs. relatives, IGT and diabetes Caballero AE et al. Diabetes 1999;48:1856-62 2005. American College of Physicians. All Rights Reserved.
Endothelial Activation
Controls vWF (%) ET-1 (pg/mL) ICAM (ng/mL) VCAM (ng/mL) 110 49 4.8 2.9 222 57 661 176 Relatives 103 41 9.4 8.7* 251 89 747 171* IGT 121 45 10.7 10.5* 264 56* 759 254 Diabetes 135 51* 10.9 10.8* 301 106* 831 257*
vWF = von Willebrand factor; Mean SD *P<0.05 Caballero AE et al. Diabetes 1999; 48: 1856-62 2005. American College of Physicians. All Rights Reserved.
THUS A major goal of treatment of pre-diabetes and diabetes is to prevent both the micro- and macrovascular complications!
Pathogenesis/Pathophysiology Type 2 Diabetes Mellitus is a Progressive Disease
Progression to Type 2 Diabetes

Genetics Insulin resistance Hyperinsulinemia Compensated insulin resistance Normal glucose tolerance Impaired glucose tolerance Genetics -cell "failure" Type 2 diabetes Insulin resistance Hepatic glucose output Insulin secretion
FFA = free fatty acid. Kruszynska Y, Olefsky JM. J Invest Med. 1996;44:413-428. 2005. American College of Physicians. All Rights Reserved.
Acquired Obesity Sedentary lifestyle Aging
Acquired Glucotoxicity FFA levels Other
Early Insulin Secretion Increases With Decreasing Insulin Action

500
Insulin Secretion AIR (U/mL)
400 300 200 100 0 1
Non-Progressors NGT NGT NGT Progressors

2 3 4 5
NGT IGT DIA
Insulin Sensitivity M-low (mg/kg EMBS per minute)

Weyer C, et al. J Clin Invest. 1999;104:787794.
Natural History of Type 2 Diabetes in Pima Indians

Progressors (n = 17)
(U/mL) Acute Insulin Response ( U/mL)
300 250 200 150 100 50 0
*P < 0.05; **P < 0.01
Non-Progressors (n = 31)
300 250
* **
200 150 100 50 0
NGT
IGT
Diabetes
NGT
NGT
NGT
Time
Weyer C, et al. J Clin Invest. 1999;104:787794.
Time
UKPDS: Progressive Deterioration in Glycemic Control Over Time

200 180 Median FPG 160 (mg/dL) 140 120 100 Time from randomization (y) Patients followed for 10 years Conventional Intensive
FPG
HbA1c
Median 8 HbA1c (%) 7
6 0 Time from randomization (y) All patients assigned to regimen Conventional Intensive
1998PPS
UKPDSGroup.Lancet.1998;352:837-853. 2005. American College of Physicians. All Rights Reserved.
-cell Function in the UKPDS

100 90 80 70 60 50 40 30 20 10 0 12 10 8 6 4 2 0 Years From Diagnosis 2 4 6
UKPDS = United Kingdom Prospective Diabetes Study. Holman RR et al. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25. 2005. American College of Physicians. All Rights Reserved.
-cell Function (%)
Strategies for Prevention
Trials to Prevent / Delay Progression From IGT to Type 2 Diabetes

Lifestyle Changes Malmo Study Da Qing Study Finnish Diabetes Prevention Study Diabetes Prevention Program Medications
Diabetes Prevention Program: metformin, (troglitazone) TRIPOD: troglitazone STOP-NIDDM: acarbose NAVIGATOR: nateglinide and valsartan DREAM: rosiglitazone and ramipril XENDOS: orlistat ORIGIN: glargine insulin ACT NOW: pioglitazone
TRIPOD = Troglitazone in Prevention of Diabetes Study; STOP-NIDDM = Study to Prevent NonInsulinDependent Diabetes Mellitus; NAVIGATOR = Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM = Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS = Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN = Outcomes Reduction with Initial Glargine Introduction. 2005. American College of Physicians. All Rights Reserved.
The Da Qing IGT and Diabetes Study

Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance
577 subjects (average BMI 25.8 Kg/m2) With impaired glucose tolerance (according to WHO criteria) Clinic assigned either to a control group or to one of three active treatment groups: diet only, exercise only, or diet plus exercise OGTT every 2 years Follow-up period 6 years
Pan et al. Diabetes Care 1997, 20(4):537-44
The Da Qing IGT and Diabetes Study

(after 6 years of intervention)
67.7%
80%
The Cumulative Incidence of Diabetes
70% 60% 50% 40% 30% 20% 10% 0%
P <0.05
43.8% 41.1% 46.0%
Control
Diet
Exercise
Diet & Exercise
Pan et al. Diabetes Care 1997, 20(4):537-44
Diabetes Prevention Study (Finnish Study)

Prevention of Type 2 DM by Changes in Lifestyle Among Subjects with IGT
522 Middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean BMI 31 kg/m2) With impaired glucose tolerance Randomly assigned to either the intervention group or the control group Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity An OGTT was performed annually; the diagnosis of diabetes was confirmed by a second test The mean duration of follow-up was 3.2 years
Tuomilehto et al. N Eng J Med 2001, 344(18):1390-2
Changes in Body Weight in the Finnish Study

1 year 2 years
P < 0.001
2 0
0.8 0.8
Change in Body Weight in Kg
-2 -4
Lifestyle
-3.5 -4.2
Control
-6 -8 -10
Cumulative Incidence of Diabetes in the Finnish Study

50%
(after 4 years of intervention)

P < 0.001
23%
The Cumulative Incidence of Diabetes
45% 40% 35% 30% 25% 20% 15% 10% 5% 0%

11%
Lifestyle
Control
58% Risk Reduction

The Finnish Study

1. The risk of diabetes is reduced by 58% in the intervention group 2. The risk reduction in the intervention group is directly linked to lifestyle changes. 3. Patients who lost 5% or more of their body weight had a 74% risk reduction 4. Patients who exceeded the recommended 4 hours exercise/week had an 80% risk reduction
The Diabetes Prevention Program

A Randomized Clinical Trial to Prevent Type 2 Diabetes in Persons at High Risk
Sponsored by the NIH, NIDDK, NIA, NICHD, IHS, CDC, ADA and other agencies and corporations
Study Population
Caucasian 1768 African-American 645 Hispanic-American 508 Asian-American & Pacific Islander 142 American Indian 171
Asian 4% American Hispanic American 16% African American 20% Caucasian 55% Indian 5%
Study Population
Age Distribution
> 60 20%
25-44 31%
45 - 59 49%
Study Interventions
Eligible participants Randomized Standard lifestyle recommendations Intensive Lifestyle (n = 1079) Metformin (n = 1073) Placebo (n = 1082)
Lifestyle & Metformin Interventions

Intensive Lifestyle Goals
Reduction of fat and calorie intake Physical activity at least 150 minutes/week Achieve and maintain at least 7% weight loss
Metformin Goals
Metformin 850 mg twice daily
Mean Weight Change

0
Weight Change (kg)
-2 -4 -6 -8 0 1 2 3 4
Y e a rs fro m R a n d o m iz a tio n
Placebo
Metformin Lifestyle
Mean Change in Leisure Physical Activity

8 MET-hours/week 6 4 2 0 0 1 2 Years from Randomization 3 4
Lifestyle
Metformin Placebo
Percent developing diabetes Incidence of Diabetes All Placebo (n=1082)

40
participants
Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac ) Lifestyle (n=1079, p<0.001 vs. Plac) Metformin , Metform in (n=1073, p<0.001 Placebo (n=1082) p<0.001 vs. Placebo)
Cumulative incidence (%)
30
20
Risk reduction 31% by metformin 58% by lifestyle
10
0 0 1 2 3 4
Years from random ization

What can we learn from the Diabetes Prevention Program?

About the prevalence of the Metabolic Syndrome in people with IGT? About the effect of the DPP interventions on the incidence and/or reversal of Met Synd?
The Effect of Metformin and Intensive Lifestyle Intervention on the Prevention of the Metabolic Syndrome: Results from the Diabetes Prevention Program
The Diabetes Prevention Program Research Group Annals Internal Medicine 2005 (in press)
Objectives
To determine the prevalence of the MS in the multiethnic DPP population of subjects with Impaired Glucose Tolerance (IGT) To evaluate the effect of the two interventions on the incidence of the MS in those subjects without the syndrome at randomization To evaluate the effect of the two interventions on the reversal of the MS in those subjects with the syndrome at randomization
Cumulative Incidence of Metabolic Syndrome by Treatment Group

Cumulative incidence of metabolic syndrome (%)
0.75
0.60
Risk reduction: 17%* by Metformin 41%# by Lifestyle Lifestyle vs. Metformin 29%#
Placebo Metformin Lifestyle
0.45
0.30
0.15
0.00 0 1 2 3 4
* p < 0.05;
p < 0.001
Year from randomization
3 year incidence (%) of components by treatment group

Placebo Waist Circ. Low HDLc High Trig. High FPG High BP 33 70 27 40 41 Metformin 15*** 67 30 29*** 44 Lifestyle 8*** 68 18*** 28*** 35***
***p<0.001,comparisonvplacebo
QUESTION Can TZDs or Other Medications Prevent or Delay the Onset of Type 2 Diabetes?
TroglitazoneInthePreventionOfDiabetes
TRIPOD: A Test of Chronic B-cell Rest Subjects Non-pregnant,non-diabeticHispanicwomen Recentgestationaldiabetes(<4years) oGTTglucosesum>medianforwomenwithGDM Procedures Placebovs400mgtroglitazonedaily Fastingglucoseeverythreemonths oGTTeveryyear ivGTTat0and3months MainOutcomeVariables Diabetesincidencerates Buchanan et al: Diabetes 51:2796-2803,2002 B-cellfunction
TRIPOD: Diabetes Rates

60%
PeoplewithDiabetes
50%
40%
Placebo
12.1%/yr
55% Reduction
20%
19% Troglitazo 5.4%/yr ne

0 10 20
0%
Buchanan et al: Diabetes, 2002
MonthsonStudy
30
40
50
60
Troglitazone in the DPP

Investigational use in DPP 1996-98 Discontinued in DPP on June 4, 1998 following fatal liver failure in a DPP participant Troglitazone participants offered group lifestyle classes (less intensive than ILS group) and same follow-up as others
Approved in USA from January 1997 to March 2000

Diabetes Cumulative Incidence

15 Cumulative Incidence (%) 10 PLAC M ET TROG ILS
31% 58%
0 0.0 0.5 1.0 1.5
75%
(2,343)
(1,568)
(739)
(237)
Years from Randomization (total no. of participants)

Diabetes Incidence During TROG Treatment Period & Beyond

15 Incidence (cases/100 p-yr) 12 9 6 3 0
July 1996May 1998 June 1998- June 1999- June 2000May 1999 May 2000 July 2001
PLAC TROG
TROG discontinued June 4, 1998
Conclusions
1. PPAR gamma Agonists do have the potential to prevent or delay the development of Type 2 Diabetes in high risk individuals. 2. Their effectiveness appears to be as good or better than lifestyle changes --BUT-3. More complete studies are needed to determine long-term effectiveness.\
STOP-NIDDM: Acarbose Reduces Diabetes Risk

1.00
25% reduction in RR Acarbose
Cumulative Probability of No Diabetes
0.90 0.80 0.70 0.60 0.50 0.40

0 100 200 300 400
Placebo
P = .0022
500
600
700
800
900 1000 1100 1200 1300
Days After Randomization

Adapted from Chiasson J-L et al. Lancet. 2002;359:2072-2077. 2005. American College of Physicians. All Rights Reserved.
STOP- NIDDM: Effect of Acarbose on the Probability of Remaining Free of CV Disease

0.06 0.05 0.04 Probability 0.03 of Any Cardiovascular 0.02 Event 0.01 0
0 100 200 300 400 500 600
Placebo 49% reduction in RR Acarbose

P = 0.04 (Log-Rank Test) P = 0.03 (Cox Proportional Model)
700 800 900 1000 1100 1200 1300 1400
Days After Randomization

No. at risk Placebo Acarbose 686 682 675 659 667 635 658 643 622 608 638 633 601 596 627 590 615 577 611 567 604 558 519 473 424 376 332 286 232 203
Chiasson J-L et al. JAMA. 2003;290:486-494. 2005. American College of Physicians. All Rights Reserved.
Summary
Worldwide epidemic of diabetes Metabolic Syndrome and IGT are more prevalent than diabetes Metabolic Syndrome, IGT and type 2 diabetes are known risk factors for cardiovascular disease Treating IGT may substantially reduce the progression to DM and potentially reduce the incidence of CV events Current strategies focus on reducing insulin resistance, and/or improving beta cell function Both Lifestyle Modification and Medications have been effective in reducing progression to DM in clinical trials, but their effectiveness in reducing CVD is not yet known
Questions For Discussion

Can Lifestyle Modification Interventions be implemented successfully? Can Lifestyle changes be sustained over long periods of time? Is Lifestyle Modification cost effective? What are the relative contributions of weight loss and increased physical activity to the beneficial effects? Should Lifestyle Modification be combined with Pharmacological Treatments to prevent type 2 diabetes and reduce CVD risk?
Approach to Treatment
Nutrition therapy decrease fat content and total calories decrease saturated fat, substitute mono/polyunsats Low glycemic index CHOs Increase dietary fiber 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
Nutrition Therapy, Exercise, Lifestyle Changes
1997PPS
New Trends in Dietary Management
There is much current interest in LOW CHO, LOW FAT and HIGH PROTEIN diets, but only limited data in humans to date. The new diabetic diet? 40% CHO:30% FAT: 30% PRO
Drugs to Treat Hyperglycemia, Correct Insulin Resistance, or Improve/Preserve B-Cell Function

Causes of Hyperglycemia in Type 2 Diabetes

2 Muscle and adipose tissue: decreased glucose uptake Insulin resistance
ntestine: glucose absorption
Blood glucose
Liver: increased hepatic glucose output
Insulin resistance 3 Pancreas: impaired insulin secretion
1997PPS
DeFronzoRA.Diabetes. 1988;37:667-687. LebovitzHE.InJoslin's Diabetes Mellitus.1994:508-529. 2005. American College of Physicians. All Rights Reserved.
Pharmacotherapy Tailored for the Multiple Defects of Type 2 Phenylalanine Derivatives Meglitinides Diabetes early postprandial Restore Restore postprandial
__________
__________
insulin patterns
insulin release
Sulfonylureas
__________
Generalized insulin secretagogue
Type 2 Diabete s Physiologic Insulin Replacement Therapy
-glucosidase Inhibitors
________
Delays CHO absorption TZDs

________
Biguanide
________
Reduces hepatic Insulin resistance
Reduce peripheral insulin resistance
Trends in Antidiabetic Therapy

1995 2000
19%
40% 52%
12%
40%
4% 4%
29%
Oral Monotherapy Oral Combination Therapy Insulin/Oral Combination Therapy Insulin Only Therapy
The majority of patients will ultimately need combination therapy with oral agents and/or insulin treatment.
Effects of Metformin Monotherapy or Combination Therapy With Glyburide

Changein fastingplasma glucose(mg/dL) 20 0 -20 -40 -60 0
* * * * *
Diet+placebo
40 20 0 -20
Glyburide Metformin
Diet+metformin
* * * *
-40 -60 -80 0

Metformin+glyburide

13
17
21
25
29
13
17
21
25
29
Week *P<0.001 P<0.001glyburide-metforminvsglyburide P<0.001metforminvsglyburide P<0.01metforminvsglyburide
Week
1998PPS
DeFronzoRAetal.N Engl J Med. 1995;333:541-549. 2005. American College of Physicians. All Rights Reserved.
Change in HbA1c in Drug-Nave Patients

0.5
+0.3
Mean Change in HbA1c (%)
0 0.5 1.0 1.5

*P < 0.0001 vs placebo 0.7* 0.8*
Placebo Nateglinide 120 mg ac Metformin 500 mg tid Nateglinide 120 mg ac + Metformin 500 mg tid
1.6*
2.0
Horton ES. Diabetes Care. 2000;23(11):16601665.
Mean Changes From Baseline in HbA1c in Patients Inadequately Controlled on Metformin*

HbA1c <8% on Metformin 0 -0.4 -0.8 Placebo Nateglinide 120 mg -1.4 HbA1c 89.5% on HbA1c >9.5% on Metformin Metformin -0.1 -0.1
Mean Change From Baseline in HbA 1c (%)
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6
*Metformin 1000 mg bid. Novartis data on file.

Effects of Pioglitazone and Sulfonylurea on FBG and HbA1c

10 0 FBG -10 (mg/dL) change -20 from baseline -30 -40 -50 -60 -52 * -34 * HbA1c (%) change from baseline 6 0.2 0.0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 -1.4
Pioglitazone 30 mg + sulfonylurea
0.1
-0.8* -1.2*
Placebo + Pioglitazone 15 mg + sulfonylurea sulfonylurea *P 0.05 for comparison with placebo

1999PPS
PioglitazonePackageInsert. SchneiderRetal.Diabetes.1999;47(suppl1):A106.Abstract.
Effects of Pioglitazone and Metformin on FBG and HbA1c

5 -5 FBG -15 (mg/dL) change -25 from baseline -35 -45 -55 Placebo + metformin
*P 0.05 for comparison with placebo
1999PPS
0.2 -5 0.0 HbA1c (%) change from baseline -38 * -0.2 -0.4 -0.6 -0.8
0.2
-0.8*
Pioglitazone 30 mg + metformin
PioglitazonePackageInsert. EganJetal.Diabetes.1999;47(suppl1):A117.Abstract.
Early Addition of Rosiglitazone 4 mg to Low-dose SU: Durable Improvement in A1c up to 2 Years

7.8 7.6
Mean A1c (%)
Glipizide Up-titration (n=106) Glipizide + Rosiglitazone 4 mg (n=59)
7.4 7.2 7.0 6.8 0 0 6 12
ADA A1c goal <7%
Months
18
24
Repeated measures analysis accounting for baseline A1c , treatment, visit, and treatment-visit interaction and the correlation among visits within a patient. Baseline values reflect the average baseline A1c across all treatments as estimated using this model. RESULT (Study 135). Data on file, GlaxoSmithKline.
Early Addition of Rosiglitazone 4 mg to Low-dose SU: More Patients Reach A1c Goal <7%
60
56%
% of Patients Responded
50 40 30 20 10 0
8.5% 34%
22%
GLIP + RSG 4 mg
Goal <7% Goal < 6.5%
GLIP Up-titration
n=106

n=59
Patients received Avandia 4 mg QD plus glipizide 10 mg BID (n=59; baseline A1c 7.6%) versus up-titrated glipizide (n=106; baseline A1c 7.6%) in a 2-year, randomized, double-blind, parallel-group study. Values represent patients meeting goal at their last observation in the study. Based on the design of this study, patients may have received 4 mg or 8 mg Avandia in combination with glipizide. Doses of Avandia greater than 4 mg daily in combination with a sulfonylurea have not been approved. A1c at last observation in study. GLIP=glipizide RESULT (Study 135). Data on file, GlaxoSmithKline. 2005. American College of Physicians. All Rights Reserved.
Rosiglitazone Added to Metformin :Long Term (HbA1c )

Rosiglitazone 8 mg/day + Metformin (N = 88) Open-Label, 30-Month Completer Analysis*
9.0 8.6 8.2 7.8 7.4 7.0 0 3 6 9 12 15 18 21 24 27 30
Rosiglitazone Added
HbA1c (%)
Time (mo)
* Patients who received rosiglitazone 4 mg BID plus metformin 2.5 g/day for at least 30 months during a double-blind, randomized study (6 months duration) and/or its open-label extension. Results of this trial are biased because they include only those patients who elected to continue on rosiglitazone plus metformin for the full duration. Patients demonstrated sustained efficacy over time in these "completers. Study/open label extensions: 093/113. Data on file, GlaxoSmithKline. 2005. American College of Physicians. All Rights Reserved.
Early Addition of Rosiglitazone 8 mg/day to 1 g Metformin: More Patients Reach A1c Goal* vs. MET Monotherapy (2 g)
% of Patients Responded 60 50 40 30 20 10 0 MET 2 g/day RSG 8 mg/day + MET 1 g/day
45%
35% 23%
55%
Goal <7% Goal <6.5%
*ADA A1c goal <7%, AACE A1C goal 6.5%. P<0.05. Patients received Avandia 8 mg/day plus metformin 1 g/day (n=322; baseline A1c 8.05%) versus maximum dose metformin (n=313; baseline A1c 7.95%) in a 24-week, randomized, double-blind, parallel-group, multicenter study.
ITT without LOCF. EMPIRE (Study 284). Data on file, GlaxoSmithKline.
Insulin Therapy in Type 2 DM

Basal insulin replacement: Glargine insulin qd or bid - NPH bid - Detemir insulin bid? Bolus insulin for meals Humalog or Novolog Regular insulin Pre-mixed insulins 70/30 or -75/25 mixtures bid or tid Insulin Pumps Inhaled insulin for meals?
New Drug Development

Incretins PPAR / dual agonists PTP-1 inhibitors GK activators Others
Incretins
Peptide hormones secreted by enteroendocrine cells in the GI tract Modulate pancreatic islet secretions as part of the enteroinsular axis Other effects on nutrient homeostasis Two major incretins that affect glucose metabolism -GLP-1: glucagon-like peptide 1 -GIP: glucose-dependent insulinotropic peptide (gastric inhibitory polypeptide)
Incretin Effect
Plasma Insulin Responses to Oral and Intravenous Glucose
Normal Weight: Non-Diabetic Subjects
90
Normal Weight: Diabetic Subjects

90
Plasma Insulin ( U/mL)
60
Plasma Insulin ( U/mL)
Oral Glucose Intravenous Glucose
Oral Glucose Intravenous Glucose
60
30
30
0 0 30 60 90 120 150 180 Time (min)
0 0 30 60 90 120 150 180 Time (min)
Non-Diabetic Subjects (glucose range 3.9-6.7 mmol/L) Diabetic Subjects (glucose range 4.7-12.2 mmol/L) Data from: Perley M, et al. J Clin Invest 1967; 46:1954-1962
Glucagon-Like Peptide-1 (GLP-1)

Product of the proglucagon gene from intestinal Lcells Release is rapid in response to meals Potent insulinotropic hormone Impaired glucose tolerance (IGT) and type 2 diabetes manifest with lower plasma GLP-1 compared to healthy controls
Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723
GLP-1 is Derived From Proglucagon

1 30 64 69 78 107/8 162 158
GRPP Glucagon IP-1

33 61 72
GLP-1
IP-2
111 123
GLP-2
158
Glicentin Oxyntomodulin
MPGF
Pancreas
Glucagon MPGF
Intestine
Glicentin Oxyntomodulin GLP-1 GLP-2 IP-2
Drucker DJ. Mol Endocrinol 2003; 17:161-171
Postprandial GLP-1 Levels are Decreased in Subjects With IGT and Type 2 Diabetes
Meal 20
* * * *
NGT subjects IGT subjects T2DM patients
* * *
15
Mean (SE) GLP-1 (pmol/L)
10
*
5
60
120
180
240
Time (min)
* P <0.05 between T2DM and NGT group.
Data from: Toft-Nielsen M, et al. J Clin Endocrinol Metab 2001; 86:3717-3723
GLP-1 secretion and metabolism

Mixed Meal
Intestinal GLP-1 Release
DPP-IV
GLP-1(7-36) Active
GLP-1(9-36) Inactive
Rapid Inactivation (>80% of pool)
Plasma
GLP-1 Actions GLP-1 Actions

DPP-IV = didpeptidylpeptidase-IV Deacon et al. Diabetes 1995; 44:1126
Renal Clearance
GLP-1 Modes of Action in Humans

Upon ingestion of food Stimulates glucose-dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying GLP-1 is secreted from the L-cells in the intestine Reduces food intake Improves insulin sensitivity Long term effects demonstrated in animals This in turn Increases beta-cell mass and maintains beta-cell efficiency
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171
Glucose Dependent Actions of GLP-1 in Patients With Type 2 Diabetes

Placebo GLP-1
Glucose (mmol/L)
17.5 15.0 12.5 10.0 7.5 5.0 2.5 0.0 -30 0 60 120 180 240
GLP-1/PBO infusion
Insulin (pmol/L)
350 300 250
GLP-1/PBO infusion
Glucagon (pmol/L)
25 20 15 10
GLP-1/PBO infusion
200
150
* *
100 50 0 -30 0
*
60
* *
*
180
*
240
5 0 -30 0
120
60
120
180
240
Time (min)
Data are mean SE. * P <0.05
Time (min)
Time (min)
Data from: Nauck MA, et al. Diabetologia 1993; 36:741-744
Effect of GLP-1 Infusion on Glucose Concentration in Patients With Type 2 Diabetes (Previously on Oral Agents)
16 14 12 Saline GLP-1 Non-diabetic Controls
Glucose (mmol/L)
10 8 6 4 2 0 22.00 24.00 02.00 04.00 06.00 08.00 10.00 12.00 14.00 16.00 Breakfast Lunch Snack
GLP-1 IV infusion (1.2 pmol/min/kg)
Clock Time (h)
Data from: Rachman J, et al. Diabetologia 1997; 40: 205-211
Strategies to Enhance Incretin Action in Diabetes

GLP-1 analogues Exendin 4 [Exenatide] DPP-IV inhibitors
Combination with metformin: Effect on A1C Over Time, ITT

9.0
Placebo 5 g exenatide 10 g exenatide
8.5
Mean (SE) A1C (%)
+ 0.1%
8.0
- 0.4%
7.5
- 0.8%
7.0
Placebo Lead-in
6.5 Screen
10
15
Time (wk)
20
25
30
ITT, N = 336 (Placebo, n = 113; 5 g exenatide, n = 110; 10 g exenatide, n = 113)
GLP-1R Agonists: Unanswered Questions

Optimal pharmacokinetics? Intermittent vs continuous administration Weight loss Sustained vs transient? Responders vs nonresponders? Islet mass and -cell function Human vs rodent data? Safety and immunogenicity?
DPP-IV
A serine protease widely expressed on cell membranes, known as CD26 DPP-IV also exists as a soluble form in plasma Prefers proline or alanine at position 2 of the Nterminus for cleavage, but can also cleave at nonpreferred amino acids Overlapping substrate specificity with several related enzymes
Localization of DPP-IV (Red) and GLP-1 (Green) in Human Gut
Circumventing DPP-IVmediated GLP-1 inactivation poses a major challenge for drug development.
Hansen L, et al. Endocrinology. 1999;140: 5356-5363. Endocrinology.
Dipeptidylpeptidase 4 (DPP4) Inactivates Glucagon Like Peptide-1 (GLP-1)

Mixed meal
Intestinal GLP-1 release
GLP-1 GLP-1 Inactive Inactive

DPP-IV DPP-IV
Rapid inactivation (>80% of pool)
GLP-1 GLP-1 Active Active

Plasma

Deacon et al. Diabetes .1995;44:1126.
Excreted by kidneys
Augmenting GLP-1 Levels by Inhibiting DPP-IV Activity

Mixed meal
Intestinal GLP-1 release
GLP-1 GLP-1 Inactive Inactive DPP-IV DPP-IV
GLP-1 GLP-1 Active Active

Plasma
Rapid inactivation (>80% of pool)
Excreted by kidneys
Deacon et al. Diabetes .1995;44:1126.
Advantages of DPP-IV Inhibition

Low risk of hypoglycemia Oral therapy, providing dosing convenience to the patient Endogenous GLP-1 levels are increased in response to meal and are transient Avoid tolerability/immunogenicity issues with exogenous GLP-1 Multiple mechanisms of GLP-1 in T2DM Insulin release is glucose dependent Reduced hepatic glucose production Improved peripheral glucose utilization Satiety effect -cell preservation / neogenesis and restoration
Source: Drucker DJ. Diabetes Care 2003;26:2929-2940.
Efficacy of LAF237 in patients with DM2 indaequately treated with metformin

42 pts received LAF plus metformin (LAF/MET) and 29 pts received placebo plus metformin (PBO/MET) for 52 wks. With LAF/MET HbA1c decreased from 7.6 to 7.1% and with PBO/MET it increased from 7.8 to 8.3%. The adjusted difference in HbA1c was 1.1% (p<0.0001) and in FPG was 20 mg/dl (p<0.05). 41% of patients on LAF/MET achieved HbA1c <7.0% compared to 10.7% of patients on PBO/MET. The treatment was well tolerated without major side effects.
Pratley, R.E. EASD Meeting Abstract 182, Sept 5-9, 2004 2005. American College of Physicians. All Rights Reserved.
DPP-IV Inhibitors
What are the advantages of DPP-IV inhibitors compared with GLP-1 analogues?
DPP-IV Inhibitors
Orally available Multiple targets GLP-1 PK favorable Short vs long acting Drug overdose nontoxic No CNS side effects
GLP-1 Analogues
Injectable Single known target Higher levels of GLP-1 Longer acting, daysweeks Drug overdose problematic Potential for CNS side effects
DPP-IV Inhibition: Key Safety Issues

Processing of substrates beyond GLP-1, GIP Potential toxicities due to non-selective inhibition DPP-IV is a member of an emerging protease family Potential role for DPP-IV (CD26) in T cell activation Potential risk of impaired immune function Role of catalytic function controversial
DPP-IV Inhibitors: Unanswered Questions

Mechanism of action? GLP-1, GIP, and other targets? Appetite and body weight? Islet function and mass in human subjects? Unanticipated actions in other systems?
Recommendations from the Global Partnership for Effective Diabetes Management

Aim for good glycemic control: HbA1c <7% Monitor HbA1c every 3 months Aggressively manage hyperglycemia, dyslipidemia and hypertension to obtain best patient outcomes Refer newly diagnosed patients to specialized centers whenever possible Address the underlying pathophysiology, including treatment of insulin resistance and Beta-cell dysfunction
Control to Goal
Recommendations from the Global Partnership for Effective Diabetes Management (cont)
Treat aggressively to achieve HbA1c <7% within 6 months of diagnosis After 3 months, if patient is not at target HbA1c <7% consider combination therapy Initiate combination therapy or insulin immediately for all patients with HbA1c >9% at diagnosis Use combinations of oral antidiabetic agents with complimentary mechanisms of action Implement a multi- and interdisciplinary team approach to diabetes management with shared responsibility for achieving glucose goal
Control to Goal
BUT Glycemic Control is not enough! There is a need for Global Treatment of CVD Risk Factors in DM2!
The Need for Global Treatment to Reduce the Risk of Compications Hyperglycemia Hypertension Dyslipidemia Obesity and Diet Physical Inactivity Smoking Cessation
Targets for Lipids in Type 2 Diabetes

Target (mg/dL) Total cholesterol HDL-C LDL-C* Triglycerides optimal 150 <200 >45 <100 acceptable 200
* 70 mg/dl optional in high risk patients
1998PPS
LDL-C Lowering With Statins: Reduced CHD Events

Secondary Prevention
4S-PL
25 20
Events (%)
Primary Prevention
LIPID-PL 4S-Rx CARE-PL LIPID-Rx WOSCOPS-Rx WOSCOPS-PL
15 CARE-Rx 10 5 0 50 70 90
AFCAPS-Rx AFCAPS-PL 210
110 130 150 170 190 LDL Cholesterol (mg/dL) Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.
HPS: MAJOR VASCULAR EVENTS by LDL CHOLESTEROL & prior DIABETES

LDL cholesterol & diabetes <116 mg/dl Diabetes No diabetes 191 (15.7%) 407 (18.8%) 410 (23.3%) 252 (20.9%) 504 (22.9%) 496 (27.9%) 24% SE 3 reduction (2P<0.00001) 0.6 0.8 1.0 1.2 1.4 SIMVASTATIN PLACEBO (10269) (10267) Rate ratio & 95% CI STATIN better PLACEBO better
116 mg/dl
Diabetes No diabetes ALL PATIENTS 1025 (20.0%) 1333 (26.2%) 2033 (19.8%) 2585 (25.2%) 0.4
The Heart Protection Study Collaborative Group. Lancet. 2003;361:2005-2016.
LDL-C
Should everyone be on a statin?
UKPDS Results: Tight Blood Pressure Control

Risk Reduction*
0 10 20 30 40 50 60
Any diabetesrelated endpoint Diabetesrelateddeath Stroke Microvascular endpoints Retinopathy progression Deterioration ofvision Heart failure P=0.0046 P=0.019 P=0.013 P=0.0092 P=0.0038 P=0.0036 P=0.0043
24%
32 %
44%
37%
34% 47% 56%
*Compared with less tight control. Captopril and atenolol were equally effective in reducing risk and were equally safe in patients with diabetes.
1998PPS
UKPDSGroup.BMJ.1998;317:703-713. 2005. American College of Physicians. All Rights Reserved.
Rate of major cardiovascular events according to diastolic blood pressure (HOT) 25

20 Events/ 1000pt-yrs 15 10 5 0 80 85 90 80 85 90
Non diabetic
Diabetic
N= 18790
HanssonLetal.Lancet1998;351:1755-62
The Steno-2 Study

Eight year study of 160 patients with DM2 and microalbuminuria randomized to conventional or intensive treatment of modifiable CV risk factors (Hyperglycemia, HTN,Dyslipidemia, ACE-I, ASA) Treatment to targets using stepped-care approach Primary endpoint: composite of death from CV causes,non-fatal MI,CABG, PTCA, non-fatal stroke, amputation or vascular surgery for PAD Secondary endpoints: nephropathy, retinopathy, neuropathy (autonomic and sensory)
Gaede,PetalNEJM348:383-93,2003
Multifactorial Intervention and Treatment Goals in Type 2 Diabetes: Steno-2
50% RR
Conclusion
This means that multifactorial or global treatment to reduce the risk of vascular complications must now be the standard of care!
How Should We Treat Type 2 Diabetes and the Metabolic Syndrome to prevent CVD?
The current recommendation is to treat the individual components with established targets for: Total and LDL-Cholesterol Triglycerides and HDL-Cholesterol Hypertension Blood Glucose and HbA1C Obesity/Inactivity (no clear targets)
And Dont Forget

Healthy Diet Exercise Smoking Cessation Anti-platelet Therapy
Metabolic Syndrome & Type 2 Diabetes Its a Nightmare!

Low-grade Inflammation
Hyperglycemia
Hypertension Endothelial Dyslipidemia Dysfunction
Prothrombotic State
NASH
O. Hamdy MD
Success is Difficult BUT
THANK YOU Now its time for discussion.


Present Therapies of Type 2 Diabetes Mellitus: ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005

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Present Therapies of Type 2 Diabetes Mellitus: ACP Annual Session MTP 057&058 San Francisco, CA April 15-16, 2005

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Present Therapies of Type 2 Diabetes Mellitus

Main Topics for Discussion

Global Projections for the Diabetes Epidemic: 2003-2025

23.0 M 36.2 M 57.0%

48.4 M 58.6 M 21%

19.2 M 39.4 M 105%

39.3 M 81.6 M 108%

43.0 M 75.8 M 79%

World 2003 = 194 M 2025 = 333 M 72%

14.2 M 26.2 M 85%

7.1M 15.0 M 111%

The Dual Epidemic: Obesity and Diabetes

The Prevalence of Overweight and Diabetes over 10 Years

50.0% 45.0% 40.0%

4.0% 3.0% 2.0%

Overweight BMI >25 Kg/m2

Diabetes & Gestational Diabetes

WHAT IS DRIVING THE DUAL EPIDEMIC?

CHANGES IN OUR LIFESTYLE!

2005. American College of Physicians. All Rights Reserved.

2005. American College of Physicians. All Rights Reserved.

2005. American College of Physicians. All Rights Reserved.

2005. American College of Physicians. All Rights Reserved.

The Role of Genes vs. the Environment

2005. American College of Physicians. All Rights Reserved.

The Insulin Resistance Syndrome

ProElevated thrombotic Blood Pressure Hyperglycemia Modified from S. Grundy MD State

Metabolic Syndrome ATP III (3 of 5)

HDL-C < 40 mg/dL (M) < 50 mg/dL (F)

BP > 130/85 mmHg

Fasting Glucose >110 mg/dL *

2005. American College of Physicians. All Rights Reserved.

National Health and Nutrition Examination Survey III, 1988-1994

Age-Adjusted Prevalence is 23.7% n= 8814

Ford et al. JAMA 2002;278:356-359

2005. American College of Physicians. All Rights Reserved.

The Metabolic Syndrome in People with IGT or Diabetes

DIABETES AND CARDIOVASCULAR DISEASE

2005. American College of Physicians. All Rights Reserved.

G 200 mg/dL (newly diagnosed diabetes)

DECODE: Mortality Rate Increases With Increasing 2-Hour Glucose

5 Fasting glucose: 2-h glucose: (mmol/L) 0

<7.0 (Not DM) 7.811.0 (IGT)

<7.0 (Not DM) 11.1 (DM)

7.0 (DM) 11.1 (DM)

Seven-Year Incidence of Fatal / Nonfatal MI in Finland

50 45 40 35 7-Year 30 Incidence 25 of MI (%) 20 15 10 5 0

4% No previous MI* Previous MI No previous MI* Previous MI

Glycemia in Relation to Microvascular Disease and MI

Incidence per 1,000 patient-years

6 7 8 9 10 11 Updated mean HbA (%)

Endothelial Dysfunction is an Early Abnormality in Obesity and Pre-diabetes

2005. American College of Physicians. All Rights Reserved.

Leg Blood Flow Changes During Methacholine Infusion

% change in leg blood flow above baseline

BMI <28 BMI >28 Type 2 diabetes

0 2.5 5 7.5 10 12.5

Methacholine chloride infusion rate ( g/min)

Flow Mediated Dilation Brachial Artery

% Increase Over Baseline

Pathogenesis/Pathophysiology Type 2 Diabetes Mellitus is a Progressive Disease

2005. American College of Physicians. All Rights Reserved.