1. 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

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. 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

4. UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications
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 Risk
N=3642
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. 4

5. 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

6. 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

7. 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

8. M:\MWP-DPP-E43627_Core Platform_R5.ppt
糖尿病治療選擇-藥物治療
二○一七年四月十四日
口服 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
糖尿病 有九大類治療藥物

9. Major Targeted Sites of Oral Drug Classes
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二○一七年四月十四日
Major Targeted Sites of Oral Drug Classes
Glucose absorption
Hepatic glucose overproduction
Impaired insulin
secretion
Insulin resistance
Pancreas
↓Glucose level
Muscle and fat
Liver
Biguanides
TZDs
Sulfonylureas
Meglitinides
α-Glucosidase inhibitors
Gut
DPP-4 inhibitors
Purpose:
To provide a broad overview of the key mechanisms and targeted sites of available anti-hyperglycaemic drug classes.
Take-away:
Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve HbA1c control.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. 15
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: ; Porte D et al. Clin Invest Med. 1995;18:247–254.
References
1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.
2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:
4. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.
5. Data on file, MSD.
6. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619. 15

10. Sulfonylureas (SU) 2nd-generation
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二○一七年四月十四日
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)
1.25~20 mg /day qd or bid
Diamicron MR
(gliclazide)
80mg
30~120/day
40~320/day

11. Sulfonylureas (SU) 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 Glibenclamide
Name
Duration
(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)
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®)
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

12. 2007 AJKD guideline

13. M:\MWP-DPP-E43627_Core Platform_R5.ppt
二○一七年四月十四日
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
times/day before meal
Novonorm
(repaglinide)
1mg
0.5~4 administrated with meal 2,3,4 times/day

14. Meglitinides Nateglinide 2-6 肝代謝，16％原型由腎排出 Repaglinide 完全肝代謝，膽汁排出 Name
Duration
(hr) 代謝
Nateglinide
(Starlix®)
2-6
肝代謝，16％原型由腎排出
Repaglinide
(NovoNorm®)
完全肝代謝，膽汁排出
CKD stage 3 and CKD stage 5/ Dialysis

15. Brand name Novonorm (1mg) Starlix (120mg) Glufast (10mg) Product name
Repaglinide
Nateglinide
Mitiglinide
Dose
0.5-4 mg tid
mg tid
mg tid
Administration time
Before meal,
15-30 min
1-30 min
5 min；with meal
Tmax
0.5-1 hr hr
17 mins
T 1/2
1-1.8 hr hr
72 mins
Metabolite 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
( mg tid, 12 wks); %
(120 mg tid, 24 weeks); %
(5~10 mg tid, 52 weeks); %
BNHI price
4.98
6.5
4.87
Daily cost
14.94 ~ 59.76
19.5
14.61

16. M:\MWP-DPP-E43627_Core Platform_R5.ppt
二○一七年四月十四日
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

17. M:\MWP-DPP-E43627_Core Platform_R5.ppt
二○一七年四月十四日
Biguanide
Name
Duration
(hr) 代謝
Glucophage
(metformin)
6-12
幾乎所有原型由腎排出

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二○一七年四月十四日
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

19. 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)
完全肝代謝成無或弱活性產物，腎臟排出

20. α-Glucosidase Inhibitor
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二○一七年四月十四日
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)
Daily dose and Frequency (mg)
Glucobay
(acarbose) 50
50~100 mg tid

21. α-Glucosidase抑制劑: acarbose
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α-Glucosidase抑制劑: acarbose
二○一七年四月十四日
Name
Duration
(hrs) 代謝
Acarbose
2-6
不被吸收
Miglitol
Alpha-Glucosidase inhibitors act by suppressing the enzyme responsible for metabolizing complex carbohydrates in the small intestine. They slow or block the breakdown and absorption of carbohydrates and certain sugars thereby delaying entry of glucose into liver and muscle tissue. Side Effects include flatulence, diarrhea and abdominal pain. Hypoglycemia may result if taken with a secretagogue or insulin. The use of alpha-Glucosidase inhibitors is contra-indicated in patients with renal dysfunction, inflammatory bowel disease, colonic ulceration or cirrhosis. They should not be used in patients with serum creatinine levels >2.0 mg/dL. This class of medications is not used much in US. Generic and brand names for common Alpha-Glucosidase inhibitors include Precose for acarbose and Glyset for miglitol.
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.

22. Definition of Incretins
二○一七年四月十四日
Definition of Incretins
“Intestine-derived factors that increase
glucose-stimulated secretion of insulin ”
In ● cre ● tin
Intestine Secretion Insulin
Creutzfeldt. Diabetologia. 1985;28:565.

23. Incretin Hormones Regulate Insulin and Glucagon Levels
Pancreas
Gut
Nutrient signals
● Glucose
Hormonal signals
GLP-1
GIP
Glucagon
(GLP-1)
Insulin
(GLP-1,GIP)
Neural signals
 cells
 cells
Purpose:
To provide a high level overview of the incretin axis.
Take-away:
In response to the oral ingestion of glucose, the gut releases incretin hormones, which in turn stimulate insulin from the pancreatic β cells and suppress glucagon release from α cells.
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.
References
1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999; 20:876–913.
2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.
3. D’Alessio DA, Vahl TP. Glucagon-like peptide 1: Evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004;286:E882–E890.
4. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.
5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.
6. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

24. The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes
二○一七年四月十四日
The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Diminished Incretin Effect
Normal Incretin Effect
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1 80 60 40 20 80 60 40 20
nmol/L
nmol/L
IR Insulin, mU/L
IR Insulin, mU/L 60
120
180 60
120
180
Time, min
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.
References:
1. Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366.
2. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52.

25. M:\MWP-DPP-E43627_Core Platform_R5.ppt
二○一七年四月十四日
DPP-4 Inhibition
作用機轉
上市產品
釋出活性Incretin
GLP-1與GIP 進食
腸胃道
DPP-4 酵素
無活性
GLP-1 X
Sitagliptin
（DPP-4 抑制劑） 胰臟
GIP
β細胞
α細胞
Drug
Dose
(mg)
Daily dose and Frequency (mg)
JANUVIA (sitagliptin)
100
100mg QD
ONGLYZA (saxagliptin)
2.5-5mg
2.5-5mg QD

26. M:\MWP-DPP-E43627_Core Platform_R5.ppt
DPP-4 Inhibition
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二○一七年四月十四日
Name
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
1#QD # QD # QD
Onglyza:
Moderate or severe CKD, or ESRD under hemodialysis: 2.5mg QD(post-H/D)
PD: no data

27. M:\MWP-DPP-E43627_Core Platform_R5.ppt
GLP-1 Analogues
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二○一七年四月十四日
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)
Daily dose and Frequency (mg)
BYETTA (exenatide)
5-10mcg
BID

28. M:\MWP-DPP-E43627_Core Platform_R5.ppt
二○一七年四月十四日
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 ?

29. 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)

30. 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

31. Insulin Action: Comparison of New Insulin Analogs
Rapid (Lispro, Aspart)
Regular
Intermediate (NPH)
Long
Insulin Level (U/ml)
Hours

32. Action Profiles Preparations Onset(h) Peak(h) Duration(h)
Lispro/Aspart <
Regular
NPH
Ultralente < 20
Glargine > 24
A variety of human insulins that can be incorporated into a basal-bolus regimen that mimicks natural islet cell function are available1
Genetically engineered short-acting human insulin preparations generally show a rapid onset of action and duration of action ranging from 3 to 4 hours1
Lantus® (insulin glargine) activity is peakless and has an onset of action beginning 1 to 2 hours after subcutaneous injection1
Lantus has demonstrated a duration of activity that is almost twice as long as that of NPH2
The absorption of Lantus, which has a 24-hour duration of action, is prolonged without unwanted peaks3 and thus mimicks physiologic basal insulin more closely than does NPH
Modified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
1. Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:
3. Lantus® (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.

33. Insulin therapy in renal disease

34. 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

35. 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 ↓)

36. 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%

37. 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

38. The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin38

39. 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

40. 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

41. New ADA/EASD algorithm for T2DM: Basal insulin is recommended for insulin initiation
At diagnosis:
Lifestyle + Metformin
+ Basal insulin
+ Sulfonylureas
+ Intensive insulin
Tier 1: well-validated therapies
STEP 1
STEP 2
STEP 3
Tier 2: Less well validated therapies
+ Pioglitazone
No hypoglycaemia
Oedema/CHF
Bone loss
Lifestyle + metformin
+ GLP-1 agonist
Weight loss
Nausea/vomiting
+ Sulfonylurea
Nathan et al. Diabetes Care 2008.
Nathan DM, et al. Diabetologia 2009;52:17−30

42. 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
The following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents.
Step 1 – initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost.
Step 2 – additional therapy within 2–3 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals.
Step 3 – further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive.
Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711–21.

43. Normal Insulin Secretion: The Basal-Bolus Insulin Concept
The basal–bolus insulin regimen
Breakfast
Lunch
Dinner
Physiological insulin
Prandial insulin 45
Basal insulin 30
Insulin (mU/L) 15
06:00
12:00
18:00
24:00
06:00
Time
Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21

44. Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile
400 20
T2DM
300 15
Plasma glucose (mg/dl)
200
Hyperglycaemia due to an increase in fasting glucose
Plasma glucose (mmol/l) 10
100 5
Normal
In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations.
Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy.
Hirsch I, et al. Clin Diabetes 2005;23:78–86.
Meal
Meal
Meal
06.00
10.00
14.00
18.00
22.00
02.00
06.00
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.

45. Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile
400 20
300 15
Plasma glucose (mg/dl)
200
T2DM
Hyperglycaemia due to an increase in fasting glucose
Plasma glucose (mmol/l) 10
100 5
Normal
Long-acting basal insulin
In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations.
Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy.
Hirsch I, et al. Clin Diabetes 2005;23:78–86.
Meal
Meal
Meal
06.00
10.00
14.00
18.00
22.00
02.00
06.00
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.

46. 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.

47. Insulin Therapy for
Type 2 Diabetes: Rescue, Augmentation, and Replacement of Beta-Cell Function

48. Type 2 Diabetes Phase III
Destiny of Type 2 Diabetes Pancreatic -Cell Decline Over Time in UKPDS
100
Insulin therapy 75
Rescue
-Cell function (%)
Augmentation 50
Replacement 25
Postprandial Hyper-
glycemia
Type 2 Diabetes Phase I
Type 2 Diabetes Phase II
Type 2 Diabetes Phase III
IGT
–12
–10 –6 –2 2 6 10 14
Years from diagnosis
Adapted from Lebovitz H. Diabetes Rev 1999;7:

49. Augmentation therapy Rescue therapy May reverse glucose toxicity
Using replacement regimens for several weeks
May reverse glucose toxicity
Augmentation therapy
With basal insulin
If some β- cell function remains
Starting dose: u/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

50. 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 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:

51. Effect of Insulin vs. OADs on HbA1c in Newly Diagnosed T2DM
Insulin group
Oral antidiabetic drug group 14
P=0.002
P=0.009 12 10
HbA1c (%) 8 6 4 2
Before therapy months months
Chen HS, et al. Diabetes Care 2008; 31:

52. Significantly Improved β-cell Function with Basal Insulin Assessed by OGTT
140
120
100 80 60 40 20 # *
Time (minutes)
Plasma insulin (mU/mL)
OAD group, after 6-month treatment
OAD group, at baseline
Insulin group, after 6-month treatment
Insulin group, at baseline
Insulin group
OAD group
*P<0.05 between groups
#P<0.05 baseline vs. after treatment
Chen HS, et al. Diabetes Care 2008; 31:

53. Replacement therapy Required for β- cell exhaustion
With basal - bolus insulin (MDI)
Required for β- cell exhaustion
Starting dose : 0.5u/kg/d
Basal % TDD
Bolus % TDD
(% of estimated calories for each meal)
Fasting  Preprandial  Postprandial
Adjustment

54. When to Consider Prandial Insulin A1C Versus FPG
240
Increase
Basal
210
180
Fasting plasma glucose (mg/dL)
Start
Prandial
150
Biphasic
Basal plus
Basal/bolus
Target
120 6 7 8 9 10
A1C (%)

55. Early Insulin Replacement in Type 2 DM May Preserve Beta-cell Function
 Glucose output
“ Beta-cell rest ”
? +
Early insulin
replacement
Reduced strain ?
Reduced toxicity ?
-> Sustained insulin
secretion
-glucosidase inhibitors (e.g. acarbose) – delay digestion and absorption of carbohydrates in the gastrointestinal tract.1,2
Sulfonylureas and meglitinides – stimulate insulin secretion from the pancreas.1,2
Biguanides (e.g. metformin) – suppress liver glucose output, enhance insulin sensitivity in the liver and stimulate insulin-mediated glucose disposal. They do not stimulate insulin secretion.1,2
Thiazolidinediones – decrease insulin resistance in fat, muscle and liver. In addition, they improve estimates of -cell function.1,2
1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Glucose uptake
 Insulin resistance
 Lipolysis
After Gerstein & Rosenstock

56. Lantus (Insulin Glargine)

57. Insulin Glargine Structure
Substitution
Extension
A chain
B chain 1 15 10 5 20
Asn 30
Gly
Arg 19 25
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
McKeage K et al. Drugs. 2001;61:

58. Insulin Glargine vs NPH clear solution vs suspension
NPH Glargine NPH NPH

59. Injection of an acidic solution (pH 4.0) 
Mechanism of Action
Injection of an acidic solution (pH 4.0) 
Microprecipitation of insulin glargine in sub-cutaneous 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.

60. Time-Action Profile of Lantus vs. NPH
Plasma glucose
Lepore et al. Diabetes 2000; 49:

61. 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 kg/m2
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

62. 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 0 (baseline)
Week 24 (endpoint)
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:

63. LEAD - Primary variable : change in HbA1c
Insulin glargine
(n=220)
NPH insulin
(n=223)
-1.2 -1
-0.8
-0.6
-0.4
-0.2
Reduction in mean HbA1c (%)
- 0.77
- 0.99
p=0.0319
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

64. LEAD: change in mean daily blood glucose (FAS)
p=0.0018
- 94
- 80
Baseline
Endpoint 50
100
150
200
250
300
276
269
189
182
Mean daily blood glucose (mg/dL)
Insulin glargine
(214)
NPH insulin
(219)
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

65. LEAD: Mean Basal Insulin Dose
Mean initial dose
Mean basal
of basal insulin*
insulin dose at
endpoint
(IU/day)
(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:

66. LEAD: Hypoglycemic Events
200
400
600
800
1000
1200
p<0.004
p<0.0003
p<0.001
Number of hypoglycemic episodes
p<0.03
All Symptomatic Severe Nocturnal
Insulin glargine NPH insulin
Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

67. Follow-up assessments
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 EASD 2008
Wednesday 12.30, Poster session

68. Glargine + glulisine (n=106)
LACE: glargine + glulisine vs premixes improved glycemic control with similar safety
Glargine + glulisine (n=106)
Premixes (n=91) p
Baseline HbA1c (%)
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
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)
(USD)
(USD)
Cost difference
–225 (USD)
Insulin pre-treated patients with T2DM (n=197)
Lee et al. Poster presentation PS 085. Abstract EASD 2008

69. 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
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 / 2.45
eGFR (ml/min/1.73m2)
27.7 27
Urine Protein/Cr ratio
1.3
1.49
Cholesterol/TG (mg/dl)
148/323
125/111
HDL/LDL (mg/dl)
26/76
28/80
Na/K (mEq/L)
139/3.9
137/4
P (mg/dl)
3.0
3.6
Albumin (g/dl)
3.5 4

70. The Basal / Basal Plus strategy for T2DM
Stepwise intensification of treatment for continuity of control
FBG at target
HbA1c above target
FBG at 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

71. Expected HbA1c Reduction in CKD
Interventions Expected decrease in HbA1c
Lifestyle – 2 %
Insulin – 3.5 %
Sulfonylureas (glurenorm) – 2 %
Glinides – 1.5 %
Sitagliptin – 0.8 %
a-glucosidase inhibitors – 0.8 %
Pioglitazones – 1.4 %
ADA: Managing hyperglycemia in T2DM
This consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM.
Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used.
An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible.
Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost.
Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1)
Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2)
Nathan DM, et al. Diabetologia 2009;52:17−30
1. Nathan DM et al. Diabetologia. 2006;49:
2. Nathan DM. N Engl J Med. 2007;356:

72. 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!

73. 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

74. ) ) ) ) ) ) ) ) ) ) ) ) )
Paradigm 512™
Paradigm Link™
Wireless Diabetes Managing System: Insulin Pump (Paradigm 512) and Blood Glucose Monitor (Paradigm Link)

75. Thank You for Your Attention!

76. Expected HbA1c Reduction
Interventions Expected decrease in HbA1c
Lifestyle – 2 %
Insulin – 3.5 %
Metformin – 2 %
Sulfonylureas – 2 %
Pioglitazones – 1.4 %
a-glucosidase inhibitors – 0.8 %
Exenatide – 1 %
Glinides – 1.5 %
Pramlintide – 1 %
Sitagliptin – 0.8 %
ADA: Managing hyperglycemia in T2DM
This consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM.
Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used.
An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible.
Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost.
Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1)
Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2)
Nathan DM, et al. Diabetologia 2009;52:17−30
1. Nathan DM et al. Diabetologia. 2006;49:
2. Nathan DM. N Engl J Med. 2007;356:

77. 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 beta-cell function
Hepatic glucose over-production
Relative Contributions of Diabetes Pathophysiologies Over Time
This is a conceptual slide about the relative contributions of diabetic pathophysiologies, beta-cell dysfunction, insulin resistance, and hepatic glucose overproduction.
Build 1-From UKPDS, at the time of diagnosis of type 2 diabetes and 6 years afterwards about 50% and 73% of beta-cell function has been lost, respectively.1 This and other data2,3 has led to the projection that beta-cell dysfunction begins in individuals with normal glucose tolerance (NGT) more than 10 years before diagnosis.1 Beta-cell dysfunction is progressive with time.3,4
Build 2-Insulin resistance, like beta-cell dysfunction, begins years before diagnosis4
Build 3-Insulin resistance develops rapidly. It has been shown that there is no significant difference between the level of insulin resistance found in individuals with impaired glucose tolerance (IGT) and that found in type 2 diabetes patients.3 Although insulin resistance is known to drive metabolic deterioration in the development of type 2 diabetes, beta-cell dysfunction ultimately determines the onset of hyperglycemia and is a major factor associated with progressively rising plasma glucose levels and disease progression.3,5
Basal hepatic glucose output did not differ significantly between NGT and IGT groups.6 It has been shown that during type 2 diabetes increases in hepatic glucose production correlate with the increases in fasting glucose levels.7
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: ; Butler AE et al. Diabetes 2003;52: ; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:
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
References:
Bell DSH. The case for combination therapy as first-line treatment for type 2 diabetic patients. Treat Endocrinol 2006;5:131–137.
Butler AE, Jansen J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110.
Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role of thiazolidinediones. Diabetes Tech Ther 2004;6:719–131.
Gastaldelli A, Ferranninni E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: Results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–39.
Rhodes CJ. Type 2 diabetes—A matter of β-cell life and death? Science 2005; 307:380–384.
Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 1992;326:22–29.
Halter JB, Ward WK, Porte D, et al. Glucose regulation in non-insulin-dependent diabetes mellitus: Interaction between pancreatic islets and the liver. Am J Med 1985;79S2B:6–12.

78. Decline of -cell function determines the progressive nature of T2DM (UKPDS)
100
Time of diagnosis ?
% of Normal by HOMA
-cell function 80
- 5% per yr 60
Pancreatic function
= 50% of normal 40 20
Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function with T2DM over time.
At the time of diagnosis, -cell function is already reduced by about 50% and continues to decline regardless of therapy.
Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.
UKPDS Group. Diabetes 1995;44:1249―58.
―10 ―8 ―6 ―4 ―2 2 4 6
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.

79. 健 康 生 活 型 態 之 飲 食 及 運 動 2010 中華民國糖尿病學會臨床指引 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
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
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