Type 2 Diabetes Update Prevention and Treatment

Bruce W. Bode, MD, FACE

Atlanta Diabetes Associates

Atlanta, Georgia

Causes of Death in People With Diabetes

Geiss LS, et al. In: Diabetes in America, 2nd ed. 1995. Bethesda, MD: National Institutes of Health; 1995:chap 11.

00

1010

2020

3030

4040

5050

%%of Deathsof Deaths

Ischemic Ischemic Heart DiseaseHeart Disease

Other Other Heart Heart

DiseaseDisease

DiabetesDiabetes CancerCancer StrokeStroke InfectionInfection OtherOther

55

Type 2 Diabetes: Two Principal Defects

Reaven GM. Physiol Rev. 1995;75:473-486Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.

Insulin resistance-cell dysfunction/

failure

± Environment ± Environment

IGT IGT

GenesGenes

Type 2 diabetesGlucose

Toxicity

Glucose

Toxicity

Role of Free Fatty Acids in HyperglycemiaRole of Free Fatty Acids in Hyperglycemia

Boden G. Proc Assoc Am Physicians. 1999;111:241-248.

MUSCLEMUSCLELIVERLIVER

FFA oxidation FFA oxidation

Gluconeogenesis Glucose utilization

Hyperglycemia

ADIPOSE TISSUEADIPOSE TISSUE

Lipolysis

FFA mobilization

Liver insulin resistance

Adipose tissue insulin resistance

Muscleinsulin resistance

HbA1c in the UKPDS

06

7

8

9

0 3 6 9 12 15

HbA

1c (

%)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

UKPDS: -Cell Function for the Patients Remaining on Diet for 6 Years

0

20

40

60

80

100

-10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6

Years After Diagnosis

-C

ell F

un

ctio

n (

%

)

Adapted from UKPDS Group. Diabetes. 1995; 44:1249-1258.

N=376

Multiple factors may drive progressive decline of -cell function

-cell(genetic background)

Hyperglycaemia(glucose toxicity)

Proteinglycation

Amyloiddeposition

Insulin resistance

“lipotoxicity”elevated FFA,TG

*Percent risk reduction per 0.9% decrease in HbA1C; UKPDS. Lancet. 1998;352:837-853.

Lowering HbALowering HbA1C1C Reduces Risk Reduces Risk of Complicationsof ComplicationsR

ed

ucti

on

in

ris

k (

%)*

p=0.029

p=0.0099

p=0.052

p=0.015

p=0.000054

0

-10

-20

-30

-40

-50

-12

-25

-16

-34

-21

Any diabetes-related endpoint

Microvascular endpoint

MI

Retinopathy

Albuminuria at 12 years

United Kingdom Prospective Diabetes Study United Kingdom Prospective Diabetes Study (UKPDS)(UKPDS)

Metformin Prevents Heart Attacks and Reduces Deaths in Type 2 Diabetes

0

5

10

15

20

0

2

4

6

8

10

Inci

den

ce(p

er 1

,00

0 p

atie

nt y

ears

)

39%Reduction

P=0.01

50%Reduction

P=0.02

Heart Attacks Coronary Deaths

Conventional MetforminTherapy

Conventioal Metformin Therapy

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

Diabetes Prevention Program

58% prevention with diet (low fat) and exercise (2.5 hours per week)

31% prevention with metformin (more effective if < 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.

Resistant SensitiveInsulin Sensitivity

Preventing Diabetes after GDMThe Strategy

Workload Reductionfor the Pancreas

1

2

Insu

lin S

ecre

tion

Troglitazone In the Prevention Of DiabetesTRIPOD: A Test of “Workload Reduction” for B-cells

Subjects Non-pregnant, non-diabetic Hispanic women Recent gestational diabetes (< 4 years) 5-year diabetes risk = 70% (oGTT glucose sum)

Procedures Placebo vs 400 mg troglitazone daily Fasting glucose every three months oGTT every year ivGTT at 0, 3, 24 months, Dx of diabetes and study end

Main Outcome Variables Diabetes incidence rates

Azen et al: Contr Clin Trials, 1998

Preventing Diabetes: The “TRIPOD” Study

Months on Study

Peo

ple

with

Dia

bete

s 53%

19%

RR=0.44Placebo12.3%/yr

Troglitazone5.4%/yr

60%

40%

20%

0%0 10 20 30 40 50 60

Randomization

Placebo Troglitazone

Small Change Large Changein S

Iin S

I

Small Fall in Large Fall inInsulin Levels Insulin Levels

DM Rate

DM Rate DM Rate

9.8%/yr

5.8%/yr 0%/yr

DM Rate12.3%/yr

Baseline 3 Months

Troglitazone Group

DM Rate: 9.8% per year DM Rate: 5.8% per year DM Rate: 0% per year

31% 32% 26%

20% 14% 0%

0.30 0.04 0.008

Fraction with Diabetes

Expected:

Observed:

p-value:

Non-Responders

IVG

TT

In

suli

n A

rea

Minimal Model SI

Responders

Small Fall in Insulin

Minimal Model SI

Responders

Large Fall in Insulin

Minimal Model SI

Early Changes in Insulin Sensitivity and Insulin Secretion and Subsequent Diabetes Rates

On Trial Off Trial

Placebo

Troglitazone(Protected)

TRIPOD Off-Trial Follow-up Study

Months after Randomization

Fra

ctio

n w

ith

Dia

bete

s

DiabetesMasking

Prevention

Observed=2.4%

37%Predicted

9%Predicted

40%

30%

20%

10%

0%

0 10 20 30 40

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”

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 ReinforcementMisscheduling, Mismanagement

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 >8% (If Seen)

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

ACE / AACE Targets for Glycemic Control

HbA1c < 6.5 %

Fasting/preprandial glucose < 110 mg/dL

Postprandial glucose < 140 mg/dL

ACE / AACE Consensus Conference, Washington DC August 2001

Goals in Management of Type 2 Diabetes

Fasting BG < 110 mg/dL

Post-meal < 140 mg/dL

HbA1c < 6.5%

Blood Pressure < 130/80

LDL < 100 mg/dl

HDL > 45 mg/dl

Sulfonylureas

Repaglinide

LiverMetformin

Rosiglitazone

Pioglitazone

Pancreas

Acarbose

Miglitol

Gut

MuscleRosiglitazone

Pioglitazone

Metformin

Hyperglycemia

Adiposetissue

Glucoseuptake

FFA output

RosiglitazonePioglitazone

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.

Insulin secretion

Glucose absorption

Hepatic glucose output

Glucose uptake

Oral Therapy for Type 2 Diabetes Target Sites of Action

Normal Type 2 Diabetes

Courtesy of Wilfred Y. Fujimoto, MD.

Visceral Fat Distribution Normal versus Type 2 Diabetes

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

VisceralObesity

InsulinResistance

Free Fatty Acids

Ath

erosclero

sisThe Metabolic Syndrome:A Network of Atherogenic Factors

Brunzell J, Hokanson J. Diabetes Care. 1999;22(Suppl 3):C10-3.McFarlane S, et al. J Clin Endocrinol Metab. 2001;86(2):713-8.Frohlich M, et al. Diabetes Care. 2000 Dec;23(12):1835-9.Kuusisto J, et al. Circulation. 1995;91:831-7.Parulkar AA, et al. Ann Intern Med. 2001;134:61-71.Hseuh WA, et al. Diabetes Care. 2001 Feb;24(2):392-7.Lebovitz H. Clin Chem. 1999;45(8B):1339-45.

Saltiel & Olefsky. Diabetes 1996;45:1661–9

Thiazolidinediones: Mode of Action

PPAR

– Affects glucose, lipid and protein metabolism

PPAR

– Affects lipoprotein metabolism (some TZDs)

Peroxisome Proliferator-Activated Receptors Peroxisome Proliferator-Activated Receptors

TZD

PPAR RXR

PPAR RXR

TZD

TF

INSULIN

RECEPTOR

Protein– signaling– downstream events

RNA

DNA

TZD - thiazolidinedionePPAR RXR - nuclear receptorsTF - transcription factors

Saltiel & Olefsky. Diabetes 1996;45:1661–9

Thiazolidinediones: Mechanism of Insulin Sensitization

Thiazolidinediones:Rationale 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 1996;45:1661–9Sonnenberg and Kotchen. Curr Opin Nephrol Hypertens 1998;7(5):551–5

-1.01

-0.54

-1.01

-1.60

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Changes in HbA1C at Endpoint in All Treated Patients

* p0.05

ACTOSACTOS™™ (pioglitazone HCl) U.S. Clinical Trials (pioglitazone HCl) U.S. Clinical Trials

HbA1C

at week 26(% points)

Daily dose ofACTOS

*

**

-0.27 -0.27

-0.86

0.74

0.20

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

Placebo (n = 79)

7.5 mg (n = 80)

15 mg (n = 79)

30 mg (n = 85)

45 mg (n = 76)

Change from Baseline Difference from Placebo

*

*

*

LOCF

Takeda Pharmaceuticals America, Data on file Study 001

Change in Lipid Profile at Endpoint: ACTOS Added to Sulfonylurea

10.15

4.07

-0.95

7.02

2.33

12.00

6.57

-15.89-20

-10

0

10

20

SU + Placebo (n = 187)

SU + ACTOS 30 mg from baseline at 16 weeks

HDL cholesterol LDL cholesterolTriglycerides Total cholesterol

*

*

(n = 189)

(%)

Baseline (mg/dL) 258.6 126.5123.741.842.9214.4211.5259.5

Takeda Pharmaceuticals America, Data on file Study 010

LOCF* p 0.05 vs. placebo

Mean Triglycerides Over Time

Error bars = SE; *Given in divided doses; Study 080, 100-week completer analysis Data on file; GlaxoSmithKline

Me

an

tri

gly

ceri

des

(m

g/d

L)

Treatment week

0 12 28 40 52 64 76 88 1000

50

100

150

200

250

300

350

RSG 8 mg/day* (n=45)Gly (n=35)

MET, metformin; TRO, troglitazone; *p=0.04; **p=0.01;Kim DD, et al. Diabetes. 2000;49:Abstract 459.

Differential Effects on Insulin SensitivityG

luco

se d

isp

osa

l rat

e

(mg

/kg

/min

)

02468

101214

MET TRO

***

+20% +44%

05

1015202530354045

MET TRO

*

Fas

tin

g p

lasm

a in

sulin

(uU

/mL

)

Baseline16 weeks

+6% -21%

Fas

tin

g p

lasm

a F

FA

(meq

/L)

00.10.20.30.40.50.60.7

MET TRO

*

+9% -24%

Assessed by Glucose Disposal, Plasma Insulin and FFA

Differential Effects on Endogenous Glucose Production

MET, metformin; TRO, troglitazone; Inzucchi SE, et al. N Engl J Med. 1998;338:867-872.

-25

-20

-15

-10

-5

0MET TRO

Ch

an

ge

in e

nd

og

en

ou

sg

luc

os

e p

rod

uc

tio

n (

%)

p=0.001

p=0.04

p=ns

Incidence of Edema

1.2 2.1 2.57.06.0

15.3

7.54.8

0

20

40

60

80

100

Placebo

ACTOS

28/373 10/1684/1604/187 58/37913/1873/259 29/606

U.S. Placebo-controlled Studies

ACTOSACTOS™™ (pioglitazone HCl) Summary of Adverse Events (pioglitazone HCl) Summary of Adverse Events

(%)(%)

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

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.

Case 1 Cont’d

2.Hypertriglyceridemia

Simvastatin therapy with TG of 402 mg/dL

Pioglitazone added

TG levels fell to 140 mg/dL

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/dLTchol 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.

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

Patient Case 3 Cont’d

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).

Approach to Combination Oral Therapy

Intensifying of Oral Therapies

m etform in &/or glitazone+

sulfonylurea/repaglinide&/or glucosidase inh

sulfonylurea/repaglinide&/or glucosidase inh

+m etform in &/or glitazone

Continue

FPG < 120 m g/dl HbA1c < 7.0% FPG > 120 m g/dl HbA1c >7.0%

Add Insulin

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

Mimicking Nature

The Basal/Bolus Insulin Concept

6-16

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 > 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

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 < 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 unitsRiddle et al, Diabetes June 2002, Abstract 457-p

Treat to Target Study; A1C Decrease

8.6

7.5

7.16.9 7

6.5

7

7.5

8

8.5

9

0 5 10 15 20 25 30

Weeks in Study (N=756)

Mea

n H

bA

1c%

Riddle et al, Diabetes June 2002, Abstract 457-p

Treat to Target Study: Patients in Target (A1C < 7%)

2.5

32.3

48.8

66.2

57

0

10

20

30

40

50

60

70

Percentage of Patients

Week 0 Week 8 Week 12 Week 18 Week 24

Riddle et al, Diabetes June 2002, Abstract 457-p

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

Advancing Basal/Bolus Insulin

Indicated when FBG acceptable but– HbA1c > 7% or > 6.5%

and/or– SMBG before dinner > 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?

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

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

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

Correction Bolus Formula

Example:

–Current BG: 220 mg/dl

– Ideal BG: 100 mg/dl

–Glucose Correction Factor: 40 mg/dl

Current BG - Ideal BGGlucose Correction factor

220 - 100 40

=3.0u

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

Conclusion

Intensive therapy is

the best way to treat

patients with diabetes