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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
1. Goal and guideline of Diabetes
treatment
2. OADs mechanism and dose adjustment
in Patients with Advanced Kidney Disease
3. Insulin therapy in Patients with
Advanced Kidney Disease
2
Outline
1. Goal and guideline of Diabetes
treatment
2. OADs mechanism and dose adjustment
in Patients with Advanced Kidney Disease
3. Insulin therapy in Patients with
Advanced Kidney Disease
3
UKPDS: Improving HbA1c Control
Reduced Diabetes-Related Complications
Relative Risk
EVERY 1%
reduction in HbA1c
N=3642
REDUCED RISK
(P<0.0001)
Diabetesrelated
deaths
1%
Myocardial
infarctions
Microvascular
complications
Amputations or deaths
from peripheral
vascular disorders
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.
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4
2007 AJKD guidelines
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)
5
5
2007 AJKD guidelines
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)
6
6
Outline
1. Goal and guideline of Diabetes
treatment
2. OADs mechanism and dose adjustment
in Patients with Advanced Kidney Disease
3. Insulin therapy in Patients with
Advanced Kidney Disease
7
糖尿病治療選擇-藥物治療
口服
糖尿病
有九大類治療藥物
1.磺醯尿素類Sulfonylurea(SU)
2. Meglitinides
3. 雙胍類Biguanide
4. Thiazolidinediones(TZD)
5. α-glucosidase inhibitors
6. 腸泌素增強劑 (DPP-4 inhibitor)
固定劑量複方藥物
注射劑
7.胰島素insulin
8.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
8
Major Targeted Sites of Oral Drug Classes
Pancreas
Impaired insulin
secretion
Sulfonylureas
Liver
Hepatic glucose
overproduction
Biguanides
Meglitinides
DPP-4 inhibitors
↓Glucose level
Gut
TZDs
DPP-4 inhibitors
Glucose
absorption
Muscle
and fat
Insulin
resistance
TZDs
Biguanides
α-Glucosidase
inhibitors
Biguanides
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Buse 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.
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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)
30mg
80mg
30~120/day
40~320/day
10
Sulfonylureas (SU)
Name
Glibenclamide
(Diabitin®)
Gliclazide
(Diamicron® MR)
Glipizide
(Minidiab®)
Glimepiride
(Amaryl®)
Duration
(hr)
代謝
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
12-18
原型由肝代謝為無活性，然後6080％由腎排出，20％由糞便排出
12-18
原型由肝代謝為無活性，然後由腎
排出
24
原形由肝代謝成弱活性，2/3由尿
液排出，1/3從糞便
11
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
Novonorm
(repaglinide)
1mg
3 times/day before meal
0.5~4
administrated with meal
2,3,4 times/day
13
Meglitinides
Name
Nateglinide
(Starlix®)
Repaglinide
(NovoNorm®)
Duration
(hr)
代謝
2-6
肝代謝，16％原型由腎排出
2-6
完全肝代謝，膽汁排出
CKD stage 3 and 4
CKD stage 5/ Dialysis
14
Brand name
Novonorm (1mg)
Starlix (120mg)
Glufast (10mg)
Product name
Dose
Administration
time
Repaglinide
0.5-4 mg tid
Before meal,
15-30 min
Nateglinide
60-120 mg tid
Before meal,
1-30 min
Mitiglinide
2.5-10 mg tid
Before meal,
5 min；with meal
Tmax
T 1/2
Metabolite
enzyme
Drug interaction
0.5-1 hr
1-1.8 hr
CYP3A4 (major)、2C8
Metabolites in
urine
Safety
- hypoglycemia
- GI intolerance
Efficacy
- HbA1C
BNHI price
Daily cost
0.25-1 hr
1.25-2.9 hr
CYP 2C9 (70%)、
3A4(30%)
Gemfibrozil, macrolide,
Warfarin,
cyclosporin, -conazole,
phenytoin, RosuCCB, ator- & sim-vastatin and flu-vastatin
8-10 %
80-83 %
17 mins
72 mins
CYP 2C9＜25%
UGT 1A 3 or 9 (74%)
No significant
interaction
16-31 %
2-5 %
(0.25-4 mg tid, 12 wks);
-1.7 %
4.98
5.5 %
3.2 %
(120 mg tid, 24
weeks); - 0.7 %
6.5
5.6 %
1.4 %
(5~10 mg tid, 52
weeks); - 1.5 %
4.87
14.94 ~ 59.76
19.5
14.61
93 % (inactive)
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
Name
Glucophage
(metformin)
Duration
(hr)
代謝
6-12
幾乎所有原型由腎排出
17
Thiazolidinediones (TZDs)
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 qd
18
Thiazolidinediones (TZDs)
Name
Duration
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
19
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
Glucobay
(acarbose)
Dose
(mg)
50
Daily dose and
Frequency (mg)
50~100 mg tid
20
α-Glucosidase抑制劑: acarbose
Duration
(hrs)
代謝
Acarbose
2-6
不被吸收
Miglitol
2-6
不被吸收
Name
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.
21
Definition of Incretins
“Intestine-derived factors that increase
glucose-stimulated secretion of insulin ”
In cre tin
●
●
Intestine Secretion Insulin
22
Creutzfeldt. Diabetologia. 1985;28:565.
Incretin Hormones Regulate
Insulin and Glucagon Levels
Hormonal signals
• GLP-1
• GIP
Glucagon
(GLP-1)
Neural signals
 cells
 cells
Gut
Pancreas
Insulin
(GLP-1,GIP)
Nutrient signals
●
Glucose
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.
23
The Incretin Effect Is Diminished
in Individuals With Type 2 Diabetes
Control Subjects
(n=8)
Patients With Type 2 Diabetes
(n=14)
Normal Incretin Effect
80
0.6
80
Diminished Incretin Effect
0.6
60
0.3
40
0.2
20
60
0.4
0.3
40
0.2
20
0.1
0
0
0
60
120
180
nmol/L
0.4
IR Insulin, mU/L
0.5
nmol/L
IR Insulin, mU/L
0.5
0.1
0
0
0
Time, min
60
120
180
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
IR = immunoreactive
Adapted 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
進食
腸胃道
釋出活性Incretin
GLP-1與GIP
β細胞
α細胞
X
Sitagliptin
（DPP-4 抑
制劑）
無活性
GLP-1
上市產品
胰臟
DPP-4 酵
素
無活性
GIP
Drug
Dose
(mg)
Daily dose and
Frequency (mg)
JANUVIA (sitagliptin)
100
100mg QD
ONGLYZA (saxagliptin) 2.5-5mg 2.5-5mg QD
25
DPP-4 Inhibition
Duration
(hrs)
代謝
JANUVIA
(Sitagliptin)
12-24hrs
70-80%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
Name
1#QD
0.5# QD
Onglyza:
Moderate or severe CKD, or ESRD under
hemodialysis: 2.5mg QD(post-H/D)
PD: no data
0.25# QD
26
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
Daily dose and
Frequency (mg)
BID
27
GLP-1 Analogues
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
?
28
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
1. Goal and guideline of Diabetes
treatment
2. OADs mechanism and dose adjustment
in Patients with Advanced Kidney Disease
3. Insulin therapy in Patients with
Advanced Kidney Disease
30
Insulin Action:
Insulin Level (U/ml)
Comparison of New Insulin Analogs
140
Rapid (Lispro, Aspart)
120
100
Regular
80
Intermediate (NPH)
60
Long
40
20
0
0
2
4
6
8
10
Hours
12
14
16
31
Action Profiles
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
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
Insulin therapy in renal disease
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
34
Insulin therapy in renal disease
 The American College of Physicians
recommended:
GFR (mL/min)
Insulin
50-10 mL/min
25% decrease
<10 mL/min
50% decrease
Haemodialysis
require less exogenous
insulin ( peripheral
insulin resistance ↓)
35
Insulin therapy in renal disease
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
Insulin therapy in renal disease
↓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
Algorithm for the Initiation and
Adjustment 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
Tier 1: well-validated therapies
At diagnosis:
Lifestyle + Metformin
Lifestyle + Metformin
Lifestyle + Metformin
+ Basal insulin
+ Intensive insulin
Lifestyle + Metformin
+ Sulfonylureas
STEP 1
STEP 2
STEP 3
Tier 2: Less well validated therapies
Lifestyle + Metformin
+ Pioglitazone
No hypoglycaemia
Oedema/CHF
Bone loss
Lifestyle + metformin
+ GLP-1 agonist
No hypoglycaemia
Weight loss
Nausea/vomiting
Lifestyle + metformin
+ Pioglitazone
+ Sulfonylurea
Lifestyle + metformin
+ Basal insulin
Nathan et al. Diabetes Care 2008.
Nathan DM, et al. Diabetologia 2009;52:17−30
ADA-EASD Consensus
Key messages on insulin
- 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
Normal Insulin Secretion:
The Basal-Bolus Insulin Concept
The basal–bolus insulin regimen
Breakfast
Lunch
Dinner
Insulin (mU/L)
45
Physiological insulin
Prandial insulin
Basal insulin
30
15
0
06:00
12:00
18:00
Time
Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21
24:00
06:00
Treating Fasting Hyperglycemia Lowers
the Entire 24-hour Plasma Glucose Profile
400
T2DM
300
15
200
Hyperglycaemia due to an increase in fasting glucose
100
10
5
Normal
0
06.00
Meal
Meal
10.00
14.00
Meal
18.00
22.00
02.00
Time of day (hours)
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.
0
06.00
Plasma glucose (mmol/l)
Plasma glucose (mg/dl)
20
Treating Fasting Hyperglycemia Lowers
the Entire 24-hour Plasma Glucose Profile
400
300
15
200
Hyperglycaemia due to an increase in fasting glucose
T2DM
100
0
06.00
10
5
Meal
Meal
10.00
14.00
Meal
18.00
Plasma glucose (mmol/l)
Plasma glucose (mg/dl)
20
Normal
Long-acting basal insulin
22.00
02.00
Time of day (hours)
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.
0
06.00
ADA/EASD Consensus Algorithm
for Type 2 Diabetes Mellitus
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
Nathan D, et al. Diabetologia 2006;49:1711−21.
Insulin Therapy for
Type 2 Diabetes: Rescue,
Augmentation, and Replacement
of Beta-Cell Function
Destiny of Type 2 Diabetes Pancreatic
-Cell Decline Over Time in UKPDS
100
Insulin therapy
75
Rescue
Augmentation
50
Replacement
25
IGT
0
–12 –10
Postprandial Type 2
Type 2
HyperDiabetes Diabetes
glycemia Phase I Phase II
–6
–2
0
2
6
Type 2
Diabetes
Phase III
10
14
Years from diagnosis
Adapted from Lebovitz H. Diabetes Rev 1999;7:139-153.
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
Insulin group
Oral antidiabetic drug group
11.89 11.33
14
HbA1c (%)
12
10
P=0.002
P=0.009
6.33 7.50
6.78 7.84
6 months
12 months
8
6
4
2
0
Before therapy
Chen HS, et al. Diabetes Care 2008; 31: 1927-1932.
Plasma insulin (U/mL)
Significantly Improved β-cell Function
with Basal Insulin Assessed by OGTT
OAD group, after 6-month treatment
OAD group, at baseline
Insulin group, after 6-month treatment
Insulin group, at baseline
140
120
#
100
#
80
#
60
*
40
*
*
#
Insulin group
*
#
#
OAD group
#
*P<0.05 between groups
#P<0.05 baseline vs. after treatment
20
0
#
0
30
Chen HS, et al. Diabetes Care 2008; 31: 1927-1932.
60
90
120
Time (minutes)
Replacement therapy
With basal - bolus insulin (MDI)
Required for β- cell exhaustion
Starting dose : 0.5u/kg/d
Basal 50-60% TDD
Bolus 40-50% TDD
(% of estimated calories for each meal)
Adjustment
Fasting  Preprandial  Postprandial
When to Consider Prandial Insulin
Fasting plasma glucose (mg/dL)
A1C Versus FPG
240
210
Increase
Basal
180
150
120
Biphasic
Basal plus
Basal/bolus
Start
Prandial
Target
6
7
8
A1C (%)
9
10
Early Insulin Replacement in Type 2 DM
May Preserve Beta-cell Function
 Glucose output
“ Beta-cell rest ”
Early insulin
replacement
?+
After Gerstein & Rosenstock
Reduced strain ?
Reduced toxicity ?
-> Sustained insulin
secretion
Glucose uptake
 Insulin resistance
 Lipolysis
Lantus
(Insulin Glargine)
Insulin Glargine Structure
Gly
A chain
1
5
10
15
5
10
10
15
15
20 Asn
Substitution
B chain
1
19
25
30
Extension
 Asparagine at position A21 replaced by glycine

Arg Arg
– 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.
Insulin Glargine vs NPH
clear solution vs suspension
NPH
Glargine
NPH
NPH
Mechanism of Action
Injection of an acidic
solution (pH 4.0)

Microprecipitation of
insulin glargine in subcutaneous tissue (pH 7.4)

Slow dissolution of free
insulin glargine hexamers
from microprecipitates
(stabilised aggregates)

Protracted action
Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.
Time-Action Profile of Lantus vs. NPH
Glucose Infusion Rate
Plasma Glucose
Plasma
glucose
12
24
10
mmol/l
mol/Kg/min
NPH
16
glargine
8
8
0
0
8
16
24
0
Time (hours)
sc injection
8
16
Time (hours)
24
sc injection
Lepore et al. Diabetes 2000; 49: 2142-2148
LEAD STUDY
Lantus Evaluation in Asian type 2 Diabetics
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 regimen
Subjects (n=448) were randomized to receive
Bedtime insulin glargine+breakfast glimepiride (3mg)
Bedtime NPH insulin + breakfast glimepiride (3 mg)
Week –4 to
week –1
Week 24
(endpoint)
Week 0
(baseline)
Screening phase
Treatment phase
Insulin starting dose: 0.15 U/kg/day
Dose titration target: FBG < 120 mg/dL (6.7 mmol/L )
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118
Reduction in mean HbA1c (%)
LEAD - Primary variable : change in HbA1c
Insulin glargine
NPH insulin
(n=220)
(n=223)
0
-0.2
-0.4
-0.6
-0.8
- 0.77
-1
- 0.99
-1.2
p=0.0319
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118
LEAD: change in mean daily
blood glucose (FAS)
Mean daily blood glucose (mg/dL)
p=0.0018
- 94
300
- 80
276
269
Baseline
Endpoint
250
200
189
182
150
100
50
0
Insulin glargine
NPH insulin
(214)
(219)
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118
LEAD: 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
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118
Number of hypoglycemic episodes
LEAD: Hypoglycemic Events
1200
p<0.004
p<0.0003
1000
800
p<0.001
600
400
200
p<0.03
0
All
Insulin glargine
Symptomatic
Severe
Nocturnal
NPH insulin
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118
LACE: prospective, randomized real-life study of
glargine + glulisine vs premixes
•
•
•
•
•
Age  18 years
HbA1c  7%
Type 2 diabetes
BMI ≥ 26
Excluded if already taking
exenatide or pramlintide
GLAR + GLU ± orals or ± other (as naturally occurring)
n = 197
Premix ± orals or ± other (as naturally occurring)
Randomization
Initial assessment
3 month
6 month
9 month
Follow-up assessments
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 2008
Wednesday 12.30, Poster session
LACE: glargine + glulisine vs premixes improved
glycemic control with similar safety
Glargine +
glulisine (n=106)
Premixes
(n=91)
p
Baseline HbA1c (%)
9.25
9.25
–
Final adjusted HbA1c (%)
6.93
7.52
0.009
Change in HbA1c (%)
–2.27
–1.68
–
Patients with
hypoglycemia (last
month)
36%
43%
NS
74
85
0.267
10.82 (USD)
12.06 (USD)
0.209
1933.20 (USD)
2158.74 (USD)
Total insulin dose/day (U)
Cost per day (all meds)
Total cost (6 months)
Cost difference
Insulin pre-treated patients with T2DM (n=197)
–225 (USD)
Lee et al. Poster presentation PS 085. Abstract 1003. EASD 2008
Case of DMN: Insulin as Initial therapy
• 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
FBS (mg/dl) / HbA1c (%)
BUN/Creatinine (mg/dl)
eGFR (ml/min/1.73m2)
Urine Protein/Cr ratio
Cholesterol/TG (mg/dl)
HDL/LDL (mg/dl)
Na/K (mEq/L)
P (mg/dl)
Albumin (g/dl)
Before Lantus
(2008/10/9)
237 / 13.2
38 / 2.42
27.7
1.3
148/323
26/76
139/3.9
3.0
3.5
After Lantus
(2009/11/26)
103 / 5.9
29 / 2.45
27
1.49
125/111
28/80
137/4
3.6
4
The Basal / Basal Plus strategy for T2DM
Stepwise intensification of
treatment for continuity of
control
FBG at target
FBG at target
HbA1c above target
HbA1c above target
Basal bolus
Basal + three prandial
FBG above target
HbA1c above target
Basal Plus
Add prandial insulin at main meal
HbA1c above target
Basal
Add basal insulin and titrate
OHA monotherapy and combinations
Lifestyle changes
Progressive deterioration of ß-cell function
OHA=oral hypoglycemic agent
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257−64
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 512™
Paradigm Link™
Wireless Diabetes Managing System:
Insulin Pump (Paradigm 512) and
Blood Glucose Monitor (Paradigm Link)
74
Thank You for Your Attention!
Expected HbA1c Reduction
Interventions
Lifestyle
Insulin
Expected decrease in HbA1c
1–2%
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
Relative Contributions of Diabetic
Pathophysiologies Over Time
Both beta-cell
dysfunction + insulin
resistance start years
before diagnosis
Beta-cell dysfunction
determines the onset of
hyperglycemia, glucose levels
and disease progression, not
insulin resistance
Those who
develop DM have
lost ~50% of betacell function
Hepatic glucose over-production
100%
Beta-cell dysfunction
100%
Insulin resistance
NGT
IGT
T2D Diagnosis
Late Stage T2DM
NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetes
Bell 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;6:719-731
Gastaldelli 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
Decline of -cell function determines
the progressive nature of T2DM (UKPDS)
% of Normal by HOMA
-cell function
100
Time of diagnosis
?
80
- 5% per yr
60
40
Pancreatic function
= 50% of normal
20
0
―10
―8
―6
―4
―2
0
2
Time (years)
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.
4
6
醣化血色素 < 9.0 % 之患者
醣化血色素 ≧9.0 % 之患者
健
康
生
活
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
使用基礎 (及/或) 餐前胰島素
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
型
態
之
未達到控制目標時
未達到控制目標時
未達到控制目標時
未達到控制目標時
飲
食
及
運
動
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
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。
2010 中華民國糖尿病學會臨床指引
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