insulin glargine in the management of hyperglycemia in type 2 diabetes 林志慶醫師 m.d. ph.d....

Insulin Glargine in the Management of Hyperglycemia

in Type 2 Diabetes

林志慶醫師 M.D. Ph.D.

國立陽明大學醫學院內科學系台北榮民總醫院內科部腎臟科

Outline

2

Outline

3

UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications

44

UKPDS=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.

EVERY 1%

reduction in HbA1c

REDUCED RISK(P<0.0001)

1%

Diabetes-related deaths

Myocardial infarctions

Microvascular complications

Amputations or deaths from peripheral

vascular disorders

21%

14%

37%

43%

Relative RiskN=3642

2007 AJKD guidelines

55

Target HbA1c for people with diabetes should be < 7.0%, irrespective of the presence or absence of CKD. (A)

Lowering HbA1c levels to approximately 7.0% reduces the development of microalbuminuria. (Strong)

2007 AJKD guidelines

66

Lowering HbA1c levels to approximately 7.0% reduces the development of macroalbuminuria. (Moderate)

Lowering HbA1c levels to approximately 7.0% reduces the rate of decrease in GFR.(Weak)

Outline

7

糖尿病治療選擇 - 藥物治療

8

糖尿病有九大類治療藥物

口服1. 磺醯尿素類 Sulfonylurea(SU)2. Meglitinides3. 雙胍類 Biguanide4. Thiazolidinediones(TZD)5. α-glucosidase inhibitors6. 腸泌素增強劑 (DPP-4 inhibitor)固定劑量複方藥物

注射劑7. 胰島素 insulin8. 胰淀素 pramlintide*9.GLP-1 作用劑 (exenatide)

吸入型胰島素 (inhaled insulin)7.Exubera®** 未在台灣上市

Major Targeted Sites of Oral Drug Classes

9Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.

DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.

Glucose absorption

Hepatic glucoseoverproduction

Impaired insulinsecretion

Insulinresistance

Pancreas

↓Glucose level

Muscle and fatLiver

Biguanides

TZDs Biguanides

Sulfonylureas

Meglitinides

TZDs

α-Glucosidase inhibitors

Gut

DPP-4 inhibitors

DPP-4 inhibitors

Biguanides

15

Sulfonylureas (SU) 2nd-generation作用機轉：胰島素分泌促進劑 (secretagogues)刺激尚有功能的 β 細胞釋放出胰島素

副作用低血糖 ( 不論血糖高糖，皆會刺激胰島素分泌，因而增加低血糖發生率 )體重增加、光敏感、噁心、頭疼、皮疹

Drug Dose Daily dose/Frequency (mg)

Amaryl(glimepiride)

2mg 1~4mg qd

Glidiab/Minidiab(glipizide)

5mg 2.5~40mg /day qd or bid

Glurenorm(gliquidone)

30mg 15~120 mg qd

Euglucon/Daonil(glyburide)

5mg 1.25~20 mg /day qd or bid

Diamicron MR(gliclazide)

30mg80mg

30~120/day40~320/day

10

11

NameDuration

(hr)代謝

Glibenclamide(Diabitin®)

12-18原形由肝臟代謝為弱活性，代謝物60％由膽汁排泄， 40％由尿液排

泄

Gliclazide(Diamicron® MR)

12-18 原型由肝代謝為無活性，然後 60-80％由腎排出， 20％由糞便排出

Glipizide(Minidiab®)

12-18 原型由肝代謝為無活性，然後由腎排出

Glimepiride(Amaryl®)

24 原形由肝代謝成弱活性， 2/3由尿液排出， 1/3從糞便

Sulfonylureas (SU)

2007 AJKD guideline

12

Meglitinides 作用機轉 : 胰島素分泌促進劑 ; 隨餐血糖調節劑

與 SU 相近的方式刺激 insulin 分泌快速吸收與作用迅速而短暫 (faster onset and shorter duration vs. SU) ，必需在進食前服藥血糖量愈低，釋出的胰島素量愈少降低餐後血糖濃度

副作用低血糖 ( 但比 SU 比例少，因其為短效藥物 ) 、體重增加

製劑Drug Dose(mg) Daily dose/Frequency (mg)

Starlix(nateglinide)

120 120 3 times/day before meal

Novonorm(repaglinide)

1mg 0.5~4 administrated with meal 2,3,4 times/day

13

14

NameDuration

(hr)代謝

Nateglinide(Starlix®)

2-6 肝代謝， 16％原型由腎排出

Repaglinide(NovoNorm®)

2-6 完全肝代謝，膽汁排出

Meglitinides

CKD stage 3 and 4 CKD stage 5/ Dialysis

Brand name Novonorm (1mg) Starlix (120mg) Glufast (10mg)Product name Repaglinide Nateglinide MitiglinideDose 0.5-4 mg tid 60-120 mg tid 2.5-10 mg tid Administration time

Before meal, 15-30 min

Before meal,1-30 min

Before meal,5 min ； with meal

Tmax 0.5-1 hr 0.25-1 hr 17 minsT 1/2 1-1.8 hr 1.25-2.9 hr 72 minsMetabolite enzyme

CYP3A4 (major) 、 2C8 CYP 2C9 (70%) 、 3A4(30%)

CYP 2C9 ＜ 25%UGT 1A 3 or 9 (74%)

Drug interaction Gemfibrozil, macrolide, cyclosporin, -conazole, CCB, ator- & sim-vastatin

Warfarin, phenytoin, Rosu- and flu-vastatin

No significant interaction

Metabolites in urine

8-10 % 80-83 % 93 % (inactive)

Safety - hypoglycemia - GI intolerance

16-31 %2-5 %

5.5 %3.2 %

5.6 %1.4 %

Efficacy - HbA1C

(0.25-4 mg tid, 12 wks); -1.7 %

(120 mg tid, 24 weeks); - 0.7 %

(5~10 mg tid, 52 weeks); - 1.5 %

BNHI price 4.98 6.5 4.87Daily cost 14.94 ~ 59.76 19.5 14.61 15

Biguanide Metformin 作用機轉

(1) 降低肝臟中的葡萄糖合成作用 (gluconeogenesis)(2) 降低或延遲腸道的葡萄糖吸收，減少飯後血糖上升(3) 增加週邊組織的胰島素敏感性

副作用常見初期腸胃不適 ( 噁心嘔吐、食慾不振 )腎功能不全者罕見的乳酸中毒報告

上市產品

Drug Dose(mg)

Daily dose and Frequency (mg)

Glucophage(metformin)

500 1000~2550mg/day bid or tid

16

Biguanide

17

NameDuration

(hr)代謝

Glucophage(metformin)

6-12 幾乎所有原型由腎排出

Thiazoldinediones (TZDs) 又稱為 PPAR-γ 作用劑作用機轉 :

與脂肪、肌肉、肝臟細胞核的 PPAR-γ receptor 結合，來增加肝臟、脂肪、肌肉細胞的胰島素敏感性

副作用 : 與劑量相關的體重增加輕度至中度的水腫及水份滯留

特別注意 : 會引發體液滯留，不能用在第 III 及 IV 心衰竭病人應定期檢測肝功能 (ALT 上昇至 >2.5 倍 UNL)不可用於肝功能受損病人

上市產品 :

Drug Dose(mg) Daily dose /Frequency (mg)

Avandia (rosiglitazone) 4 or 8 4~8mg/day qd or bid

Actos (Pioglitazone) 30 15~45mg qd18

Thiazolidinediones (TZDs)

19

NameDuration 代謝

Avandia (rosiglitazone) Weeks

完全肝代謝成無活性產物，腎臟排出

Actos (Pioglitazone) Weeks

完全肝代謝成無或弱活性產物，腎臟排出

Thiazolidinediones (TZDs)

α-Glucosidase Inhibitor作用機轉抑制腸內 α-glucosidase的作用 ( 分解碳水化合物的一群酵素 ) ，使碳水化合物在腸道被分解為單糖和吸收延遲 ;可降低糖尿病患者飯後的血糖濃度

副作用腸胃副作用 ( 腹痛、腹瀉、脹氣 )

上市產品

Drug Dose(mg)


Glucobay(acarbose)

50 50~100 mg tid

20

α-Glucosidase 抑制劑 : acarbose

21

NameDuration

(hrs)代謝

Acarbose 2-6 不被吸收

Miglitol 2-6 不被吸收

Information about the long-term use of acarbose in patients with reduced kidney function is sparse and its use in patients with later stage 3 and stages 4 and 5 CKDis not recommended.

Definition of Incretins

“Intestine-derived factors that increase

glucose-stimulated secretion of insulin ”

In ● cre

● tin

Intestine Secretion Insulin

Creutzfeldt. Diabetologia. 1985;28:565.22

Incretin Hormones Regulate Insulin and Glucagon Levels

GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes CarAdapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. e. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744.

PancreasGut

Nutrient signals

● Glucose

Hormonal signals• GLP-1• GIP

Glucagon(GLP-1)

Insulin (GLP-1,GIP)

Neural signals cells

cells

23

Time, min

IR I

nsu

lin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes

Control Subjects (n=8)

Patients With Type 2 Diabetes (n=14)

Time, min

IR I

nsu

lin

, mU

/L nm

ol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 120 0

Oral glucose load Intravenous (IV) glucose infusion

Normal Incretin Effect Diminished Incretin Effect

IR = immunoreactiveAdapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–366. 24

DPP-4 Inhibition作用機轉

上市產品

25

Drug Dose(mg)


JANUVIA (sitagliptin) 100 100mg QD

ONGLYZA (saxagliptin)

2.5-5mg 2.5-5mg QD

釋出活性 IncretinGLP-1 與 GIP

進食

腸胃道

DPP-4 酵素

無活性GLP-1

XSitagliptin（ DPP-4 抑制劑）

胰臟

無活性GIP

β細胞α細胞

DPP-4 Inhibition

26

NameDuration

(hrs)代謝

JANUVIA(Sitagliptin)

12-24hrs70-80%腎臟排出，無法被透析排

出ONGLYZA(Saxagliptin)

24hrs全由肝臟代謝成無或弱活性產物，後從腎臟排出，可以被透析洗出

Onglyza:Moderate or severe CKD, or ESRD under hemodialysis: 2.5mg QD(post-H/D)PD: no data

1#QD 0.5# QD 0.25# QD

GLP-1 Analogues

作用機轉產生類似 GLP-1的作用

副作用對照性臨床研究中，不論單一或合併療法，表現出良好耐受性，出現臨床不良反應而停藥者與安慰劑相當

上市產品

Drug Dose(mg)


BYETTA (exenatide) 5-10mcg BID

27

GLP-1 Analogues

28

BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) caution in patients with renal transplantation.Moderate renal impairment (30-50 mL/min): caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcg REFERENCE: U.S. Food and Drug Administration

?

Renal Side Effects of Exenatide

11/02/2009 FDA:From April 2005 through October 2008,

FDA received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. (total number: 6.6 million)

29

Outline

30

Insulin Action: Comparison of New Insulin Analogs

0

20

40

60

80

100

120

140

0 2 4 6 8 10 12 14 16

RegularRegular

Rapid (Lispro, Aspart)Rapid (Lispro, Aspart)

Insu

lin L

evel

(In

sulin

Lev

el (

U/m

l)U

/ml)

HoursHours

Intermediate (NPH)Intermediate (NPH)

Long Long

31

Preparations Onset(h) Peak(h) Duration(h)

Lispro/Aspart < 0.25 1 - 2 3 - 4

Regular 0.5 - 1 2 - 4 6 - 8

NPH 1 - 3 5 - 7 13 - 16

Ultralente 2 - 4 8 - 14 < 20

Glargine 1 - 2 > 24

Action Profiles

Modified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.

Insulin therapy in renal disease

33


34

BiesenbachG, Raml A, Schmekal B, Eichbauer-SturmG:Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. DiabetMed 20:642–645, 2003

Insulin therapy in renal diseaseThe American College of Physicians recommended:

35

GFR (mL/min) Insulin

50-10 mL/min 25% decrease

<10 mL/min 50% decrease

Haemodialysis require less exogenousinsulin ( peripheral insulin resistance ↓)


OBJECTIVE— Type 2 diabetic patients with end-stage renal disease (ESRD) on maintenance hemodialysis.

CONCLUSIONS— The present study has demonstrated a significant

25% reduction in basal insulin requirements No significant change in boluses Overall the reduction of total insulin requirements was

15%

36


↓GFR: RI (rapid-acting insulin analogs): ↑ half-life and maximal serum concentrations NPH (Caution!): long-acting ‘‘basal’’ insulin like glargine Insulin detemir : binding to serum albumin after injection so less predictable in patients with nephrotic syndrome and hypoalbuminema

37

The ADA Treatment The ADA Treatment Algorithm for the Initiation and Algorithm for the Initiation and

Adjustment of InsulinAdjustment of Insulin

ADA-EASD Guidelines

Achievement of normal glycemic goals Initial therapy with lifestyle intervention and

metformin Early addition of insulin therapy in patients who

do not meet target goals Rapid addition of and transition to new regimens,

when glycemic goals are not achieved

Management of Type 2 Diabetes ADA-EASD

Check HbA1c every 3 months until < 7% and then at least every 6 months

Insulin regimens under lifestyle and diet control

Initiation and intensification of insulin due to effectiveness and low expense although 3 oral agents can be used

New ADA/EASD algorithm for T2DM: Basal insulin is recommended for insulin initiation

Nathan et al. Diabetes Care 2008.

At diagnosis:Lifestyle + Metformin

Lifestyle + Metformin

+ Basal insulin


+ Sulfonylureas


+ Intensive insulin

Tier 1: well-validated therapies

STEP 1 STEP 2 STEP 3

Tier 2: Less well validated therapies

Lifestyle + Metformin+ Pioglitazone

No hypoglycaemiaOedema/CHF

Bone loss

Lifestyle + metformin+ GLP-1 agonistNo hypoglycaemia

Weight lossNausea/vomiting

Lifestyle + metformin+ Pioglitazone+ Sulfonylurea

Lifestyle + metformin+ Basal insulin

Nathan DM, et al. Diabetologia 2009;52:17−30

- Insulin is the most effective drug in lowering BG

- Insulin should be started with basal insulin

- Basal Insulin is proposed as early as after Metformin

- Then consider stepwise addition of bolus insulin starting with one shot at selected meal

- Premixes are not recommended as first line insulin therapy

ADA-EASD Consensus Key messages on insulin

The basal–bolus insulin regimen

Insu

lin (

mU

/L)

06:00 12:00 24:0018:000

15

30

45

06:00

Breakfast Lunch Dinner Physiological insulin

Basal insulinPrandial insulin

Time

Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21

Normal Insulin Secretion: The Basal-Bolus Insulin Concept

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001).Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.

Time of day (hours)

400

300

200

100

006.00 06.0010.00 14.00 18.00 22.00 02.00

Pla

sm

a g

lucose (

mg

/dl)

NormalMeal Meal Meal

20

15

10

5

0

Pla

sm

a g

lucose

(mm

ol/l)

Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile

Hyperglycaemia due to an increase in fasting glucose

T2DM

Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001).Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.

Time of day (hours)

400

300

200

100

006.00 06.0010.00 14.00 18.00 22.00 02.00

Pla

sm

a g

lucose (

mg

/dl)

NormalMeal Meal Meal

20

15

10

5

0

Pla

sm

a g

lucose

(mm

ol/l)

Hyperglycaemia due to an increase in fasting glucose

T2DM

Long-acting basal insulin

Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile

ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus

Nathan D, et al. Diabetologia 2006;49:1711−21.

Initiation of Basal Insulin:

•Start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin

•Can initiate with 10 units or 0.2 units per kg

•↑ 2 units every 3 days, if 180> FBS >130 mg/dl

•↑ 4 units every 3 days if FBS >180 mg/dl

• If hypoglycaemia or FBS <70 mg/dl, ↓ bedtime

dose by 4 units, or 10% if dose >60 units

Insulin Therapy for Type 2 Diabetes: Rescue,

Augmentation, and Replacement of Beta-Cell Function

-C

ell

fun

cti

on

(%

)

PostprandialHyper-

glycemiaIGT

Type 2DiabetesPhase I

Type 2DiabetesPhase II

25

100

75

0

50

–12 –10 –6 –2 0 2 6 10 14

Years from diagnosis

Adapted from Lebovitz H. Diabetes Rev 1999;7:139-153.

Destiny of Type 2 Diabetes Pancreatic -Cell Decline Over Time in UKPDS

Type 2DiabetesPhase III

Insulin therapyRescue

Replacement

Augmentation

Rescue therapy Using replacement regimens for several weeks May reverse glucose toxicity

Augmentation therapy With basal insulin If some β- cell function remains Starting dose: 0.15-0.2u/kg/d or units of insulin/d = FBS (mmol) = FBS/18 (mg/dl) e.g. FPG 180mg/dl 10 units FPG 270mg/dl 15 units

Early Aggressive Insulin Therapy Study in Taiwan

60 newly diagnosed type 2 diabetic patients hospitalized patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10-14 days.

50 patients randomized to insulin therapy and oral antidiabetic drugs after discharge for 6 months and a follow-up for further 6 months

HbA1c and Beta-cell function were measured.

Chen HS, et al. Diabetes Care 2008; 31: 1927-1932.

Effect of Insulin vs. OADs on HbA1c in Newly Diagnosed T2DM

Hb

A1c (

%)

8

6

4

2

0

P=0.002

10

Before therapy 6 months 12 months

Insulin group

Oral antidiabetic drug group

12

14P=0.009

6.33 7.50 6.78 7.84

11.89 11.33


Significantly Improved β-cell Function with Basal Insulin Assessed by OGTT


140

120

100

80

60

40

20

00 30 60 90 120

##

#

#

###

#

***

*

Time (minutes)

Pla

sma

insu

lin (U

/mL)

OAD group, after 6-month treatmentOAD group, at baselineInsulin group, after 6-month treatmentInsulin group, at baseline

*P<0.05 between groups#P<0.05 baseline vs. after treatment

Insulin group

OAD group

Replacement therapy

With basal - bolus insulin (MDI) Required for β- cell exhaustion

Starting dose : 0.5u/kg/dBasal 50-60% TDD Bolus 40-50% TDD

(% of estimated calories for each meal)

Fasting Preprandial Postprandial

Adjustment

When to Consider Prandial Insulin A1C Versus FPG

Target

Increase Increase BasalBasal

StartPrandialPrandial

240

210

180

150

120

76 8 9 10

A1C (%)

Fas

tin

g p

lasm

a g

luco

se (

mg

/dL

)

BiphasicBasal plusBasal/bolus

Early Insulin Replacement in Type 2 DM May Preserve Beta-cell Function

Glucose uptake

Insulin resistance Lipolysis

Glucose output

Early insulin replacement

Reduced strain ?

Reduced toxicity ?

-> Sustained insulin secretion

? +

After Gerstein & Rosenstock

“ Beta-cell rest ”

Lantus(Insulin Glargine)

Insulin Glargine Structure

Asparagine at position A21 replaced by glycine– Provides stability

Addition of 2 arginines at the C-terminus of the B chain– Soluble at slightly acidic pH

Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.McKeage K et al. Drugs. 2001;61:1599-1624.

SubstitutionSubstitution

ExtensionExtension

A chainA chain

B chainB chain

11

1515101055

1010 1515

2020 AsnAsn

3030

GlyGly

ArgArg ArgArg

55 1010 1515 1919 2525

11

Insulin Glargine vs NPHclear solution vs suspension

NPH Glargine NPH NPH

Mechanism of ActionInjection of an acidic Injection of an acidic

solution (pH 4.0) solution (pH 4.0)

MicroprecipitationMicroprecipitation of of insulin glargine in sub-insulin glargine in sub-

cutaneous tissue (pH 7.4) cutaneous tissue (pH 7.4)

Slow dissolution of Slow dissolution of freefree insulin glargine insulin glargine hexamershexamers

from microprecipitates from microprecipitates (stabilised aggregates) (stabilised aggregates)

Protracted action Protracted action Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.

Time-Action Profile of Lantus vs. NPH

12

10

8

0

16

8

24

mol

/Kg/

min

Time (hours)

sc injection

Glucose Infusion Rate

0 168 24

Time (hours)

0 168 24

mm

ol/l

Plasma Glucose

sc injection

NPHNPHNPH

glargineglargineglargine

Lepore et al. Diabetes 2000; 49: 2142-2148

Plasma glucose

LEAD STUDYLEAD STUDY LLantus antus EEvaluationvaluation in in AAsian type 2 sian type 2 DDiabeticsiabetics

Inclusion criteria:Inclusion criteria:

• Asian men and women with type 2 DM, insulin-naive

• Aged > 40 and 80 years

• Treatment with OADs for at least 3 months

–Any sulfonylurea, as monotherapy or in combination with metformin or acarbose

–Previous sulfonylurea dose glimepiride 3 mg

• HbA1c between 7.5% and 10.5%

• FBG >120 mg/dL (6.7 mmol/L)

• BMI 20-35 kg/m2

Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118

LEAD: Treatment regimenLEAD: Treatment regimen

Subjects (n=448) were randomized to receive

Bedtime insulin glargine+breakfast glimepiride (3mg)

Bedtime NPH insulin + breakfast glimepiride (3 mg)

Screening phase

Week –4 to week –1

Week 0 (baseline)

Week 24 (endpoint)

Treatment phase

Insulin starting dose: 0.15 U/kg/dayDose titration target: FBG < 120 mg/dL (6.7 mmol/L )


LEAD - Primary variable : change in HbA1cLEAD - Primary variable : change in HbA1c

- 0.99

- 0.77

p=0.0319

Insulin glargine(n=220)

NPH insulin(n=223)

Red

uct

ion

in

mea

n H

bA

1c (

%)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0


LEAD: change in mean dailyLEAD: change in mean daily blood glucose (FAS)blood glucose (FAS)

Baseline

Endpoint

Insulin glargine(214)

NPH insulin(219)

Mea

n d

aily

blo

od

glu

cose

(m

g/d

L)

276 269

p=0.0018

182 189

- 94 - 80

0

50

100

150

200

250

300


LEAD: Mean Basal Insulin DoseLEAD: Mean Basal Insulin Dose

Mean initial dose of basal insulin*

(IU/day)

Mean basal insulin dose at

endpoint (IU/day)

Insulin glargine 9.6 32.1

NPH insulin 9.8 32.8

* Start dose recommended by protocol: 0.15 U/kg/day

No difference between PP and FAS population


LEAD: Hypoglycemic EventsLEAD: Hypoglycemic Events

All Symptomatic Severe Nocturnal

p<0.004

p<0.0003

p<0.001

p<0.03

Insulin glargine NPH insulin

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es

0

200

400

600

800

1000

1200


LACE: prospective, randomized real-life study of glargine + glulisine vs premixes

n = 197

Randomization

Initial assessment Follow-up assessments

3 month 6 month 9 month

GLAR + GLU ± orals or ± other (as naturally occurring)

Premix ± orals or ± other (as naturally occurring)

• Age 18 years• HbA1c 7%• Type 2 diabetes• BMI ≥ 26• Excluded if already taking exenatide or pramlintide

Note: Inclusion – All patients eligible for BOTH insulin regimens Debit cards for all participants to cover additional, initial GLU copay so patients will have equal financial access to both treatment arms

Lee et al. Poster presentation PS 085. Abstract 1003. EASD 2008Wednesday 12.30, Poster session

LACE: glargine + glulisine vs premixes improved glycemic control with similar safety

Insulin pre-treated patients with T2DM (n=197)

Glargine + glulisine (n=106)

Premixes (n=91)

p

Baseline HbA1c (%) 9.25 9.25 –

Final adjusted HbA1c (%) 6.93 7.52 0.009Change in HbA1c (%) –2.27 –1.68 –

Patients with hypoglycemia (last month)

36% 43% NS

Total insulin dose/day (U) 74 85 0.267

Cost per day (all meds) 10.82 (USD) 12.06 (USD) 0.209

Total cost (6 months) 1933.20 (USD) 2158.74 (USD)

Cost difference –225 (USD) Lee et al. Poster presentation PS 085. Abstract 1003. EASD 2008

Before Lantus (2008/10/9)

After Lantus (2009/11/26)

FBS (mg/dl) / HbA1c (%)

237 / 13.2 103 / 5.9

BUN/Creatinine (mg/dl) 38 / 2.42 29 / 2.45eGFR (ml/min/1.73m2) 27.7 27Urine Protein/Cr ratio 1.3 1.49Cholesterol/TG (mg/dl) 148/323 125/111HDL/LDL (mg/dl) 26/76 28/80Na/K (mEq/L) 139/3.9 137/4P (mg/dl) 3.0 3.6Albumin (g/dl) 3.5 4

• Mr. King, 81 y/o male, diabetic nephropathy since 2008/10• 2008/10/14, initiating Lantus 24 units qd FBS 130~160 mg/dl• 2008/12/3, adding Novonorm 1.5# tid FBS 100~120 mg/dl• 2009/11/27, maintaining Lantus 26 units qd + Novonorm 1.5# tid

Case of DMN: Insulin as Initial therapy

The Basal / Basal Plus strategy for T2DM

Lifestyle changes

OHA monotherapy and combinations

BasalAdd basal insulin and titrate

Basal PlusAdd prandial insulin at main meal

Basal bolusBasal + three prandial

FBG at target

HbA1c above target

OHA=oral hypoglycemic agent Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257−64

Progressive deterioration of ß-cell function

HbA1c above target

FBG above targetHbA1c above target

FBG at targetHbA1c above target

Stepwise intensification of treatment for continuity of control

Expected HbA1c Reduction in CKD

Interventions Expected decrease in HbA1c

Lifestyle 1 – 2 %

Insulin 1.5 – 3.5 %

Sulfonylureas (glurenorm) 1 – 2 %

Glinides 1 – 1.5 %

Sitagliptin 0.5 – 0.8 %

-glucosidase inhibitors 0.5 – 0.8 %

Pioglitazones 0.5 – 1.4 %

Nathan DM, et al. Diabetologia 2009;52:17−30

Summary: Treatment of DM in CKD

Novel diabetic medications are available in past few years.

Some require adjustment of dose or should be even avoided according to the patient’s renal function.

Metformin, 1st line Tx in patients with normal renal function, is contraindicated in CKD with Cr>1.5 (M) or 1.4 (F) mg/dL.

CKD stage 3/4: SU (glipizide, gliclazide, glimepiride), Glinides, TZD, DPP4i, α-glucosidase inhibitor, insulin

CKD stage 5 or ESRD: SU (glipizide, gliclazide), Glinide (repaglinide, mitiglinide), TZD, DPP4i, insulin

Judicious titration of medications and frequent monitoring of blood glucose to avoid severe adverse effects!

Summary for Basal Insulin Therapy

Tight glycemic control reduces risk of complications.

Earlier initiation of insulin helps achieve target of glycemic control.

Lantus, long-acting insulin analog, as a basal insulin therapy with:

– Once daily, peakless, 24 hours basal insulin– Consistent efficacy in glycemic control– Less hypoglycemia than NPH insulin and premixed

human insulin– Less adverse reactions than TZD add-on to OADs– Easy titration according to FPG to achieve target

Paradigm Link™

Paradigm 512™) ) ) ) ) ) ) ) ) )

) ) )

Wireless Diabetes Managing System: Insulin Pump (Paradigm 512) and

Blood Glucose Monitor (Paradigm Link)74

Thank You for Your Attention!

Expected HbA1c Reduction

Interventions Expected decrease in HbA1c

Lifestyle 1 – 2 %

Insulin 1.5 – 3.5 %

Metformin 1 – 2 %

Sulfonylureas 1 – 2 %

Pioglitazones 0.5 – 1.4 %

-glucosidase inhibitors 0.5 – 0.8 %

Exenatide 0.5 – 1 %

Glinides 1 – 1.5 %

Pramlintide 0.5 – 1 %

Sitagliptin 0.5 – 0.8 %Nathan DM, et al. Diabetologia 2009;52:17−30

Late Stage T2DMIGT

Insulin resistance

T2D DiagnosisNGT

Beta-cell dysfunction

100%

100%

Relative Contributions of Diabetic Pathophysiologies Over Time

Those who develop DM have lost ~50% of beta-

cell function

Beta-cell dysfunction determines the onset of

hyperglycemia, glucose levels and disease progression, not

insulin resistance

Both beta-cell dysfunction + insulin resistance start years

before diagnosis

Hepatic glucose over-production

NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetesBell D. Treat Endocrinol 2006; 5:131-137; Butler AE et al. Diabetes 2003;52:102-110; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:719-731Gastaldelli A, et al Diabetologia 2004:47:31-39; Mitrakou A, et al. N Engl J Med 1992; 326:22-29; Halter JB, et al. Am J Med 1985;79S2B:6-12

HOMA= Homeostasis model assessment.UKPDS Group. Diabetes 1995;44:1249―58. Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.

Decline of -cell function determines the progressive nature of T2DM (UKPDS)

-

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Time (years)

0

20

40

60

80

100

―10 ―8 ―6 ―4 ―2 0 2 4 6

Time of diagnosis?

Pancreatic function= 50% of normal

- 5% per yr

健健

康康

生生

活活

型型

態態

之之

飲飲

食食

及及

運運

動動

醣化血色素 < 9.0 % 之患者醣化血色素 ≧ 9.0 % 之患者

使用一種或二種口服抗糖尿病藥物• 促胰島素分泌劑• 雙胍類藥物• 胰島素增敏劑• 阿爾發葡萄醣苷酶抑制劑• 二肽基肽酶 -4 抑製劑

使用二種或多種口服抗糖尿病藥物• 促胰島素分泌劑• 雙胍類藥物• 胰島素增敏劑• 阿爾發葡萄醣苷酶抑制劑• 二肽基肽酶 -4 抑製劑

使用基礎 ( 及 / 或 ) 餐前胰島素

未達到控制目標時

增加不同種類的口服抗糖尿病藥物或單獨使用胰島素 ( 或合併使用 )• 促胰島素分泌劑• 雙胍類藥物• 胰島素增敏劑• 阿爾發葡萄醣苷酶抑制劑• 二肽基肽酶 -4 抑製劑

增加不同種類的口服抗糖尿病藥物或使用胰島素

增加不同種類的口服抗糖尿病藥物或單獨使用胰島素 ( 或合併使用 )• 雙胍類藥物• 胰島素增敏劑• 阿爾發葡萄醣苷酶抑制劑• 二肽基肽酶 -4 抑製劑

註 1: 適時調整口服糖尿病藥物和胰島素，希望使糖化血色素在 3-12 個月內達到治療的目標，若未達到治療目標，宜轉診至專科醫師。註 2: 選擇降血糖藥物需依照病人個別情況而定，避免藥物所引起的低血糖。註 3: 同時使用胰島素及胰島素增敏劑可能增加水腫的機會，並應同步注意病患的心臟功能變化。

使用基礎 ( 及 / 或 ) 餐前胰島素

增加不同種類的口服抗糖尿病藥物或單獨使用胰島素• 雙胍類藥物• 胰島素增敏劑• 阿爾發葡萄醣苷酶抑制劑• 二肽基肽酶 -4 抑製劑

未達到控制目標時未達到控制目標時未達到控制目標時

2010 中華民國糖尿病學會臨床指引79

insulin glargine in the management of hyperglycemia in type 2 diabetes 林志慶 醫師 m.d. ph.d....

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insulin glargine in the management of hyperglycemia in type 2 diabetes 林志慶醫師 m.d. ph.d....