Management of Type 2 Diabetes

Dr.Gayotri GoswamiAttending Physician,

Jacobi-North Central Bronx Hospital April 29th, 2009

Stages of Type 2 Diabetes Related to Beta-Cell Function

Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

2­12 ­2­10 ­6 0 6 10 14

Beta­Cell­Function­

(%)

0

50

100

75

25

Type­2Phase­1IGT

Years­from­Diagnosis

Type­2Phase­2

Type­2Phase­3

Postprandial

Hyperglycemia

TREATMENT­OF­T2­DMIS­NOT­JUST­TREATING­HYPERGLYEMIA

PREVENTION AND TREATMENT OF MACROVASCULAR DISEASEREQUIRES ADDRESSING ALL

CARDIOVASCULAR RISK FACTORS

HbA1c

Retinopathy

Nephropathy

NeuropathyMacrovascular disease

­­

DCCTDCCT9 7%

76%

54%

60%

41%*

­­

Kumamoto9 7%

69%

70%

-

-

­­

UKPDS8 7%

17-21%

24-33%

-

16%*

*­not­statistically­significant

Good Glycemic Control (Lower HbA1c) Reduces ComplicationsGood Glycemic Control (Lower HbA1c) Reduces Complications

UKPDS Study Group: Lancet 352:837-53, 1998Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995DCCT Study Group: N Engl J Med 329:977-86, 1993

14

Targets for Glycemic Control*Normal Goal

American­Diabetes­Association1

A1C (%)Preprandial plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL)

<6.0<110

<7.090-130<180

European­Diabetes­Policy­Group2

A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)

<6.0<110

<6.5<110<135

American­Association­of­Clinical­Endocrinologists3

A1C (%)Preprandial plasma glucose (mg/dL) Postprandial glucose (mg/dL)

<6.0<110

<6.5<110<140

*More stringent goal of <6.0% should be considered for individual patients. Generally, A1C goal for each patient is an A1C as close to normal as possible without significant hypoglycemia.A1C = glycosylated hemoglobin A1C.1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S42. 2. European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. 3. Feld S. Endocr Pract. 2002;8(suppl 1):40-82.

Major components for patient centered care

International Diabetes Center model of patient-centered team care

Metabolic Management of type 2 DM

Nathan et al, A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care,29:759-764,2006

NON-PHARMACOLOGIC­MEASURES

Diabetes Self Management Training (DSMT)

Lifestyle Interventions • Ongoing Patient Education• Medical Nutrition Therapy (MNT)• Physical Activity• SMBG

Behavioral Health• Emotional assessment• Support Needs

Medical Nutrition Therapy

• A1c has been shown to decrease by 1% in a RCT in Type 1 Diabetics

• In Type 2, a decrease in A1c of 2% in newly diagnosed cases and 1% in cases of 4 years duration

• Most effective during the early stages after diagnosis of Type 2 when insulin resistance is the highest

• Messages on physical activity and MNT should be the most aggressive during the early stages

‘Healthy Plate Concept’

Contributions of FPG and PPG to Overall Glycemia in T2DM

PPG­+­FPG­=­A1C­(%)

01020304050607080

1 2 3 4 5

A1C­Quintiles

Contribution­(%)

PPG

FPG

FPG = fasting plasma glucose. PPG: Post prandial glucoseAdapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

<7.3 7.3- 8.4 8.5 - 9.2 9.3- 10.2 >10.2

PHARMACOLOGIC­MEASURES

Sites of Action of Oral Antidiabetic Agents

Muscle­and­adipose­tissue:Peripheral­glucose­uptakeTHIAZOLIDINEDIONES

Liver:­GlucoseproductionBIGUANIDES

Pancreas:­Insulin­secretionSULFONYLUREASMEGLITINIDESAmylin­secretion

Intestine:­Digestion­and­absorption­of­carbohydrates-GLUCOSIDASE­INHIBITORS

GIT­:­Increase­glucose­stimulated­insulin­secretionINCRETIN­MIMETICS

Effect of Oral Therapies on A1c

Biguanides: inhibits hepatic glucose production, slow titration dose

• Glucophage­(metformin) 500 mg

850 mg1000 mg 500 to 2550 mg daily (b.i.d.)

• Glucophage­XR­(extended­release­delivery­system)500­mg750­mg 500­to­2000­mg­daily­(q.d.­or­b.i.d.)

-1.2

-1.7

-2.0

-1.6

-0.9

-2.5

-2

-1.5

-1

-0.5

0

0.5

Mean­Difference­in­HbA1c­(%)­vs.­Placebo­atEnd­of­Study(14­weeks)

500­mg

(n=73)

1000­mg

(n=73)

1500­mg

(n=76)

2000­mg

(n=73)

2500­mg

(n=77)

*

*

*

*

*

*P<0.001

Metformin Dose-Response Study

Mean HbA1c Reductions

Garber AJ et al., Am J Med 1997.

-32

-42-36

-39-50

-40

-30

-20

-10

0

%­Risk­

Reduction

American Diabetes Association. Diabetes Care. 1999;22(suppl 1):S27-S31.

UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865.

*­Compared­with­conventional­treatment;†­P=0.0023;­‡­P=0.017;­§P=0.011;¶­P=0.01

‡

§¶

Any­Diabetes-­ Diabetes-­ ­Related Related­ ­All-Cause ­ ­Endpoint ­Mortality­ Mortality­ MI

UKPDS:Effects of Intensive (Metformin)

Treatment*

†

Sulphonylureas

• Lower BG by increasing insulin secretion from the pancreatic beta cells

• The glucose lowering effect usually plateaus at approximately one half of the maximum recommended dose *

• Should be used cautiously in the elderly and those with hepatic or renal impairment

*Simonson et al.Diabetes care,1997;20:597-606 Stenman et al. Ann.Int.Med, 1993;118:169-172

Sulfonylureas (insulin secretagogues)

• FIRST GENERATION AGENTS- lower binding affinity to the SFU receptor and must be given in higher doses

• SECOND GENERATION AGENTS– Glucotrol­(glipizide)­ ­2.5­to­20­mg­daily­(b.i.d.)– Glucotrol­XL­(glipizide­GITS) ­2.5­to­20­mg­daily­(q.d.)– Micronase,­DiaBeta­(glyburide)­­­2.5­to­20­mg­daily­(q.d.)– Glynase­(micronized­glyburide)­­1.5­to­­­6­mg­daily­(q.d.)– Amaryl­(glimepiride­score­tabs)­­0.5­to­­­8­mg­daily­­(q.d.)

Thiazolidinediones

• Pharmacological ligands for a nuclear receptor known as the PPAR

• When activated, this receptor binds to response elements on DNA and alters transcription in various genes to regulate carbohydrate and lipid metabolism

• Through this process increase insulin stimulated glucose uptake in the skeletal muscle cells

Molecular­Targets­of­PPAR­&­PPAR­action

NEJM 2004; 351:1106-18

Thiazolidinediones

• Indicated as monotherapy and in combination with SFU, metformin & insulin

• Weight gain & edema are commonly seen when used with insulin

• Contraindicated in patients with CHF and hepatic impairment

• Additionally combining 2 sensitizers produces and additive effect*

*Einhorn et al.Clin.Ther.2000;22:1395-1409

Glinides(Nateglinide and Repaglinide)

• Rapid but short lived release of insulin that lasts 1 to 2 hours

• Attenuate post prandial glucose excursions, therefore should be used to target PP blood glucose levels

• Repaglinide (Prandin) is more potent ,is minimally cleared by the kidneys and can be used safely with severe renal impairment

Insu

lin (µ

U/m

L)In

sulin

(µU

/mL)

00 44 88 1212 1616 2020

Time (hours post-morning dose)Time (hours post-morning dose)

Nateglinide: Meal-Related Insulin Levels in type 2 diabetes

NAT 120 mg ac x 3*NAT 120 mg ac x 3*Placebo ac x 3Placebo ac x 3

(n = 10) After 1 Wk Tx(n = 10) After 1 Wk Tx

120120

100100

8080

6060

4040

2020

00

MealMeal MealMeal SnackSnack

*No dose taken with snack.*No dose taken with snack.Walter YH, et al. Walter YH, et al. Eur J Clin Pharm. Eur J Clin Pharm. 2000;56:129–133.2000;56:129–133.

MealMeal

-Glucosidase Inhibitors delays digestion of carbohydrates and slows

glucose absorption, slow titration dose• Precose (acarbose)

– 25 mg– 50 mg– 100 mg 75 to 300 mg daily (t.i.d.) before meals

• Glyset (miglitol) – 25 mg– 50 mg– 100 mg 75 to 300 mg daily (t.i.d.) before meals

-Glucosidase Inhibitors

• Long history of use• Good safety profile• No weight gain• Mild stool softening • No substantial

systemic drug-drug interaction

• Good adjunctive therapy

• Require high-carbohydrate diet

• Must be taken before every meal

• Modest efficacy

• Flatulence and GI side effects

• Elevated LFT’s have been reported

Lebovitz­HE,­Diabetes Reviews­1998.

Advantage­­ Disadvantage­

INCRETINS

GLP 1 – Glucagon like peptide 1GIP – Glucose dependant insulinotropic polypeptide

GLP-1 GIP Is­released­from­L­cells­in­ileum­and­colon1,2

Is­released­from­K­cells­in­duodenum1,2

Stimulates­insulin­response­from­beta­cells­in­a­glucose-dependent­manner1

Stimulates­insulin­response­from­beta­cells­in­a­glucose-dependent­manner1

Inhibits­gastric­emptying1,2 Has­minimal­effects­on­gastric­emptying2

Reduces­food­intake­and­body­weight2

Has­no­significant­effects­on­satiety­or­body­weight2­

Inhibits­glucagon­secretion­from­alpha­cells­in­a­glucose-dependent­manner1

Does­not­appear­to­inhibit­glucagon­secretion­from­alpha­cells1,2

1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.

42

Modulation of Insulin and Glucagon Levels: The Enteroinsular Axis

alpha­cellsalpha­cellsbeta­cellsbeta­cells

Pancreas

Gut­­­­Insulin (GLP-1,GIP)

Glucagon(GLP-1)

Nutrient­signals

Hormonal­signals•­GLP-1•­GIP

Neural­signals

Adapted­with­permission­from­Creutzfeldt­W.­Diabetologia.­1979;16:75–85.­Copyright­©­1979­Springer-Verlag.Drucker­DJ.­Diabetes Care.­2003;26:2929–2940.Kieffer­T­et­al.­Endocr Rev.­1999;20:876–913.Nauck­MA­et­al.­Diabetologia.­1993;36:741–744.

43

Time,­min

IR­Insulin,­m

U/L n

mol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The­Incretin­Effect­in­Subjects­Without­and­With­Type­2­Diabetes

Control­Subjects­(n=8)

Patients­With­Type­2­Diabetes­­(n=14)

Time,­min

IR­Insulin,­m

U/L n

mol­/­L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120­­­­­0

Oral­glucose­load

Intravenous­(IV)­glucose­infusion

Incretin­Effect

The­incretin­effect­is­diminished

in­type­2­diabetes.

Adapted­with­permission­from­Nauck­M­et­al.­Diabetologia.­1986;29:46–52.­Copyright­©­1986­Springer-Verlag.

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme

Meal

Intestinal­GIP­and­GLP-1­

release

GIP­and­GLP-1­Actions

DPP-­4Enzyme

GIP-(1–42)GLP-1(7–36)

Intact

GIP-(3–42)GLP-1(9–36)Metabolites

Rapid­Inactivation

Half-life*GLP-1­~­2­minutesGIP­~­5­minutes

Deacon­CF­et­al.­Diabetes.­1995;44:1126–1131.*Meier­JJ­et­al.­Diabetes.­2004;53:654–662.

Effective­GLP­1­therapies:

Exenatide (Byetta)– binds to and activates the GLP 1 receptor and resists degradation by DPP-4 (April 2005)

Sitagliptin (Januvia) – resistant to DPP-4 degradation (October 2006)

Vildagliptin – inhibits the DPP-4 enzyme (Under review by FDA)

Byetta (Exenatide)

• Indicated as an adjunctive therapy in patients withType 2 DM who are taking Metformin, SFU or a combination and TZDbut has not achieved adequate control

• Not recommended for use in patients with ESRD, severe renal impairment, or severe gastrointestinal disease and in Type 1 Diabetics

Byetta (Exenatide)

• Major side effect is nausea.

Recent FDA warning of acute pancreatitis being associated with Byetta.

• Prescribed as a subcutaneous injection given within 1 hour before the morning and evening meal

• Starting dose is 5 ug BID and can be increased to 10 ug BID

Sitagliptin (Januvia)DDP-4 inhibitor

• Monotherapy or in combination with Metformin, TZD, Glimepiride ± Metformin

• Mainly target PPG but have been shown to decrease FBG levels

• Daily recommended dose is 100mg orally once a day

• Dose adjustment is required in moderate to severe renal insufficiency

“Although insulin therapy has not traditionally been implemented early

in the course of Type 2 diabetes, there is no reason why it should not

be…”

Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.

Physiologic Blood Insulin Secretion Profile

Plasma­Plasma­Insulin­Insulin­((µU/mL)­U/mL)­

4:004:00

2525

5050

7575

8:008:00 12:0012:00 16:0016:00 20:00­­20:00­­ 24:0024:00 4:004:00

Breakfast Lunch Dinner

Time

8:008:00

Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

Hours­After­Glucose­Ingestion

Patients­With­Type­2­DiabetesHealthy­Subjects

Plasma­Insulin

0

20

40

60

–1 0 1 2 3 4 5

90

180

270

360

–1 0 1 2 3 4 5

Plasma­Glucose

Mitrakou A, et al. Diabetes. 1990;39:1381–1390.

Loss of Early Insulin Release Leads to Postprandial Hyperglycemia

(mU/L)(mg/dL)

INSULINS Peak­(duration)­hrs

• RAPID-ACTING­INSULIN­ANALOGS– Humalog­(lispro) 1-2­ (2-6)– Novolog­(aspart)­ 1-2­ (2-6)– Glulisine­(epidra) 1-2­­­­­­­­(2-6)

• SHORT-ACTING-­­Regular­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­ 2­-­4­ (3-6)

• INTERMEDIATE-ACTING

– NPH ­­­­­­­­­­­6-12­ (10-24)­­­­­­­­­­­

• LONG­ACTING– Lantus­/­glargine­ ­­­­­­­­­­­­none­ (10-24)– Levemir­/­detemir ­­­­­­­­­­­­­­­­­­­­­-­

Fixed dose insulin mixes

HUMULIN­(NPH/REG)

–70/30

–50/50

HUMALOG­(Prot-lispro/free­lispro)

–75/25

NOVOLIN­(NPH/REG)

–70/30

NOVOLOG­MIX­(Prot-aspart/aspart)

–70/30

Insulin delivery devices

OPTIONS………

1. Once daily background or basal insulin if fasting BG is elevated but glucose values remain stable during the day,

2. Once daily or twice daily pre-mixed insulin analogue, orally administered drugs may or may not be continued

3. Basal bolus therapy…..first initiate basal along with 1 bolus injection before the largest meal and eventually at each meal ,if needed

What doses to start with……..

• With HbA1c <8%, begin 0.1U/Kg body weight

• HbA1c 8-10%, start 0.2U/kg body weight

• HbA1c >10%, start 0.3U/Kg body weight

• With pre-mixes can divide the total dose by 2 if used twice a day

• With insulin glargine, adjust dose every 3-7 days until target fasting dose is reached

Bergenstal Endocrine Practice,Jan 2006

Advantages of rapid acting insulin analogs

• Restores the early insulin peak in combination with meal ingestion

• Prevents the hyperinsulinemia resulting from the late absorption of regular insulin and thereby protects against hypoglycemia

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Change­in­serum­insulin­

­­Baseline­Level

Theoretical­representation­of­expected­insulin­release­in­nondiabetic­subjects

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Regular­insulin­(human)

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Regular­Insulin­(human)

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­expected­insulin­release­in­nondiabetic­subjects

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­rapid-acting­Insulin­Analog

Change­in­serum­insulin­

Rapid-Acting­Insulin­Analog

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

NPH­insulin­(human)

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­NPH­Insulin

Change­in­serum­insulin­

Human Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

Human­Premix­70/30­(70%­NPH­&­30%­Regular)

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Human­Premix­70/30

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

QD­(basal)­Analog­Insulin

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Basal­Analog­Insulin

Change­in­serum­insulin­

Analog Insulin Time-Action Patterns

Time­(hours) ­SC­injection

Normal­insulin­secretionat­mealtime

­­Baseline­Level

Theoretical­representation­of­profile­associated­with­Insulin­Analog­Premix

Change­in­serum­insulin­

Insulin­Analog­Premix

USE COMBINATION THERAPY AND GET PATIENTS TO GOAL AS SOON AS POSSIBLE

COMBINATION THERAPYAACE Guidelines, Endocrine Practice, May/June 2007

• Finally, Type 2 DM is a progressive disease with worsening glycemia over time.

• Therefore, addition of medications is the rule, not the exception, if treatment goals are to be met over time.