slide1 l.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
糖尿病治療新趨勢 PowerPoint Presentation
Download Presentation
糖尿病治療新趨勢

Loading in 2 Seconds...

play fullscreen
1 / 67

糖尿病治療新趨勢 - PowerPoint PPT Presentation


  • 281 Views
  • Uploaded on

糖尿病治療新趨勢. 時間: 2009-04-24 (09:00-10:30) 地點:花蓮高中 主講人:三軍總醫院 石光中主任 (MD, PhD). MANAGEMENT OF TYPE 2 DIABETES. ORAL ANTIDIABETIC AGENTS (OAD) INSULIN. MANAGEMENT OF TYPE 2 DIABETES. ORAL ANTIDIABETIC AGENTS (OAD) INSULIN. ORAL ANTIDIABETIC AGENTS.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about '糖尿病治療新趨勢' - elu


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

糖尿病治療新趨勢

時間:2009-04-24 (09:00-10:30)

地點:花蓮高中

主講人:三軍總醫院 石光中主任(MD, PhD)

management of type 2 diabetes
MANAGEMENT OF TYPE 2 DIABETES
  • ORAL ANTIDIABETIC AGENTS (OAD)
  • INSULIN
management of type 2 diabetes3
MANAGEMENT OF TYPE 2 DIABETES
  • ORAL ANTIDIABETIC AGENTS (OAD)
  • INSULIN
oral antidiabetic agents
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
oral antidiabetic agents5
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
oral antidiabetic agents7
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
oral antidiabetic agents9
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
oral antidiabetic agents11
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
pharmacologic targets of current drugs used in the treatment of t2dm

Thiazolidinediones

Increase glucose uptake in skeletal muscle and decrease lipolysis in adipose tissue

Meglitinides

Increase insulin secretion from pancreatic -cells

Biguanide (metformin)

Decreases hepatic glucose production and increases uptake

Sulfonylureas

Increase insulin secretion from pancreatic -cells

-Glucosidase inhibitors

Delay intestinal carbohydrate absorption

Pharmacologic targets of current drugs used in the treatment of T2DM

Adapted from Cheng and Fantus. CMAJ. 2005;172:213–226.

traditional type 2 diabetes management a treat to fail approach
Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach”

Published Conceptual Approach

OAD plus

multiple daily

insulininjections

Diet andexercise

OAD

monotherapy

OAD

up-titration

OAD

combination

OAD plus

basal insulin

Mean HbA1cof patients

10

9

HbA1c, %

8

7

6

Time

Duration of Diabetes

OAD=oral anti-hyperglycaemic drug.

Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631.

Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

12

oral antidiabetic agents16
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
pramlintide
PRAMLINTIDE
  • Pramlintide, a synthetic analog of amylin, is an injectable antihyperglycemic that modulates postprandial glucose levels and is approved for preprandial use in individuals with type 1 and type 2 diabetes.
  • Pramlintidesuppresses glucagon release via undetermined mechanisms, delays gastric emptying, and has central nervous system-mediated anorectic effects.
  • It is rapidly absorbed after subcutaneous administration; levels peakwithin 20 minutes, and the durationof action is not more than 150 minutes.
  • Pramlintide should be injected immediately before eating; doses range from 15 mcg to 120 mcg subcutaneously.
pramlintide18
PRAMLINTIDE
  • Therapy with this agent should be initiated with the lowest dose andtitrated upward.
  • Because of the risk of hypoglycemia, concurrent rapid- or short-acting mealtime insulin doses should be decreasedby 50% or more.
  • Pramlintide should always be injected by itself with a separate syringe; it cannot be mixed with insulin.
  • The major side effects of pramlintide are hypoglycemiaandgastrointestinal symptoms including nausea, vomiting, and anorexia.
oral antidiabetic agents19
ORAL ANTIDIABETIC AGENTS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide(Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
glp 1 and gip are the two major incretins
GLP-1 and GIP Are the Two Major Incretins

GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide

Adapted from Drucker DJ DiabetesCare 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.

insulin secretion increases dramatically in response to oral glucose ingestion

200

400

50 g glucose

150

300

Glucose (mg/dL)

Insulin (pmol/L)

100

200

50

100

0

0

-30

0

30

60

90

120

150

180

210

-30

0

30

60

90

120

150

180

210

Time (min)

Time (min)

Insulin Secretion Increases Dramatically in Response to Oral Glucose Ingestion

Oral Glucose Tolerance Test

Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.

proof of a gastrointestinal incretin effect different responses to oral vs iv glucose

200

150

100

50

0

-30

0

30

60

90

120

150

180

210

Time (min)

Oral

IV

Proof of a Gastrointestinal ‘Incretin Effect’: Different Responses to Oral vs. IV Glucose

OGTT and Matched IV Infusion

400

300

Glucose (mg/dL)

Insulin(pmol/L)

200

100

0

-30

0

30

60

90

120

150

180

210

Time (min)

Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8.

type 2 diabetes patients have impaired glp 1 secretion
Type 2 diabetes patients haveimpaired GLP-1 secretion

n =33

n=54

Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3717–3723

glp 1 restores islet cell glucose sensing in t2 dm

Glucose (mg/dL)

C-peptide (nmol/L)

Glucagon (pmol/L)

300

30

3.0

GLP-1 infusion

GLP-1 infusion

GLP-1 infusion

250

25

2.5

*

*

200

*

20

2.0

*

*

*

150

*

15

1.5

*

*

*

100

*

10

1.0

*

*

*

*

*

GLP-1

50

5

0.5

Saline

0

0

0.0

–30

0

30

60

90

120

150

180

210

240

–30

–30

0

0

30

30

60

60

90

90

120

120

150

150

180

180

210

210

240

240

Time (min)

Time (min)

Time (min)

GLP-1 Restores Islet Cell Glucose Sensing in T2DM

*P < .05

GLP-1 = glucagon-like peptide–1; T2DM= type 2 diabetes mellitus

Adapted from Nauck MA, et al. Diabetologia. 1993;36:741–744.

glp 1 has multiple desirable effects
GLP-1 has multiple desirableeffects
  • Stimulates insulin secretion
  • Preserves or increases β-cell mass in animal models
  • Decreases glucagon secretion
  • Delays gastric emptying
  • Induces satiety and decreases food intake
  • Beneficial effects on memory and learning in animal models
glp 1 is rapidly degraded by dpp 4
GLP-1 is Rapidly Degraded by DPP-4

DPP-4

A

G

F

S

S

V

L

G

A

H

E

T

T

D

Y

E

S

Q

A

7

9

K

A

K

F

L

R

I

V

E

W

G

G

37

T½ = 1–2 minutes

*Amino acids shown in gold are homologous with the structure of glucagon.

glp 1 related agents
GLP-1 related agents
  • NN2211(Liraglutide) :

long-acting GLP-1 derivative

  • Exenatide:

synthetic exendin 4 compound

  • DPP-4 inhibitors
glp 1 related agents30
GLP-1 related agents
  • NN2211(Liraglutide) :

long-acting GLP-1 derivative

  • Exenatide:

synthetic exendin 4 compound

  • DPP-4 inhibitors
nn2211 liraglutide is a long acting glp 1 analogue
NN2211(Liraglutide) is a long-acting GLP-1 analogue

26

34

Knudsen et al. J Med Chem 2000;43:1664–1669

glp 1 related agents32
GLP-1 related agents
  • NN2211(Liraglutide)

long-acting GLP-1 derivative

  • Exenatide

synthetic exendin 4 compound

  • DPP-4 inhibitors
exenatide
EXENATIDE
  • As a synthetic analog of glucagon-like-polypeptide 1 (GLP-1), exenatide is the first incretin therapy to become available for the treatment of diabetes.
  • In clinical studies, exenatide therapy is shown to have multiple actions such as potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emptying and a central loss of appetite.
  • Exenatide is absorbed equally from arm, abdomen, or thigh injection sites, reaching a peak concentration in approximately 2 hours with a duration of up to 10 hours.
exenatide34
EXENATIDE
  • Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 mcg twice daily, with a maximum dosage of 10 mcg twice daily.
  • When exenatide is added to preexisting sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia.
  • The major side effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage.
glp 1 related agents35
GLP-1 related agents
  • NN2211(Liraglutide)

long-acting GLP-1 derivative

  • Exenatide

synthetic exendin 4 compound

  • DPP-4 inhibitors
pancreatic islet cells are targets for incretin hormones
Pancreatic Islet Cells are Targets for Incretin Hormones

β-Cell

α-Cell

Foodintake

Incretin

Pancreatic Islet

Incretin Response

GLP-1=Glucagon-Like Peptide-1

Adapted from Drucker D. Diabetes Care. 2003;26:2929-2940. Wang Q, et al. Diabetologia. 2004;47:478-487.

slide37

DPP-4 Inhibitors

Mixed meal

GLP-1

Inactive

Intestinal

GLP-1

release

DPP-IV

GLP-1

Active

Rapid inactivation

(>80% of pool)

Plasma

GLP-1 Actions

Excreted by kidneys

Improvement of glucose

metabolic profile

Mechanism of Action of DPP-4 Inhibitors

Primary actions of GLP-1

- Promote insulin secretion (β- cell) - Reduce glucagon secretion/hepatic glucose production (α- cell)

synthesis secretion and metabolism of glp 1 and gip

ProGIP

Capillary

GIP [1-42]

Synthesis, Secretion, and Metabolism of GLP-1 and GIP

L-Cell

K-Cell

Proglucagon

GLP-1 [7-37]

Capillary

GLP-1 [7-36NH2]

GIP [1-42]

ACTIVE

GLP-1[7-36NH2]

ACTIVE

DPP-4

DPP-4

  • Dipeptidyl peptidase-4 (DPP-4)
    • Ubiquitous, specific protease
    • Cleaves N-terminal dipeptide
    • Inactivates > 50% of GLP-1 in ~ 1 min
    • > 50% of GIP in ~ 7 min

GIP [3-42]

INACTIVE

GLP-1 [9-36NH2]

INACTIVE

oral antidiabetic drugs
ORAL ANTIDIABETIC DRUGS
  • Insulin secretagogues (sulfonylureas, meglitinides, D-phenylalanine derivatives)
  • Biguanides
  • Thiazolidinediones
  • α-glucosidase inhibitors
  • Pramlintide (Amylin)
  • Exenatide (GLP-1)
  • Sitagliptin (DPP-4 inhibitor)
dpp 4 inhibitors improve glucose control by increasing incretin levels in type 2 diabetes

↑insulin and ↓glucagon reduce hepatic glucose

output

GI tract

X

DPP-4

Inhibitor

DPP-4 Inhibitors Improve Glucose Control by Increasing Incretin Levels in Type 2 Diabetes

Ingestion of food

  • Glucose dependent
  • Insulin

from beta cells(GLP-1 and GIP)

Insulinincreases peripheral glucose uptake

Pancreas

Release of incretins from the gut

β-cells

Hyperglycemia

Improved Physiologic

Glucose Control

α-cells

DPP-4 Enzyme

  • Glucagon

from alpha cells (GLP-1)Glucose dependent

Inactive incretins

DPP-4 = dipeptidyl peptidase 4

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.

sitagliptin
SITAGLIPTIN
  • Sitagliptin is an inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that degrades incretin and other GLP-1-like molecules.
  • Control of hyperglycemia and reductions in HbA1c were documented at doses of 100 mg orally once daily.
  • Dosage should be reduced in patients with renal impairment. Hypoglycemic episodes were rare and the drug facilitated weight loss.
  • Sitagliptin therapy can be combined with metformin, TZDs, or sulfonylureas.
characteristics of an ideal therapy
Characteristics of an Ideal Therapy
  • Characteristics of an ideal oral antidiabetic agent
    • Lowers HbA1cto normal levels
    • Decreases insulin resistance and hepatic glucose production and increasesor preserves β-cell mass while restoring first-phase insulin response
    • Does not cause weight gain
    • Does not increase risk of hypoglycemia
    • Does not cause edema or congestive heart failure
combination therapy offers advantages over monotherapy
Combination Therapy Offers Advantages Over Monotherapy
  • Combination therapy may provide more glycemic control than the individual monotherapies
  • Combination therapy may provide more comprehensive coverage of the key pathophysiologies of type 2 diabetes than monotherapy
  • An appropriately chosen combination therapy may help more patients achieve their HbA1c goal without increasing side effects1

Adapted from Del Prato Int J Clin Pract 2005;59:1345-1355.

management of type 2 diabetes47
MANAGEMENT OF TYPE 2 DIABETES
  • ORAL ANTIDIABETIC AGENTS (OAD)
  • INSULIN
introduction
Introduction
  • Insulin replacement consists of

1. Prandial (bolus) insulin:mimic the response of endogenous insulin to food intake, but onlythe first phase of insulin secretion

2. The basal-insulin:mimics the relatively small but constant release of insulin

3.Correction-dose insulin supplement:addresses pre-meal or between-meal hyperglycemia, independentlyof the prandial insulin.

slide51

餐後血糖控制不足

易產生餐後低血糖

0900

1200

1500

1800

2100

2400

0300

0600

0600

Breakfast

Lunch

Dinner

NPH

傳統人類胰島素

Normal free insulin levels

(Mean)

Human insulin

450

Meals

300

Plasma insulin (pmol/l)

150

0

需餐前 30分鐘注射

Time of day

novorapid
NovoRapid
  • 可於餐前或餐後立即注射
  • 顯著改善餐後血糖控制
  • 有助於改善長期血糖控制
  • 大幅降低hypoglycemia發生率
  • 第一個獲得 FDA 核准使用於 pump的 insulin analogue
  • 提升患者生活品質 (Quality of life)
  • 劑量給予/ 轉換容易
long acting analogues
Long-Acting Analogues

Insulin glargine

  • The firstof the long-acting insulin analogues,insulin glargine, was introduced in the USA in the spring of 2001.
  • This analogue is produced by the substitution of glycine for asparagine at position A21of the insulin molecule and by the addition oftwo argininemolecules at position B30.
  • These changes lead to a shift in the isoelectric point toward aneutral pH, which results in an insulin molecule that isless solubleat the injection site and that precipitates in the subcutaneous tissue to form a depot from which insulin is slowly released.
new analogues
New analogues
  • Insulin detemir : Long acting, neurtral PH, acylated derivative of human insulin, requires bid injection in type 1 DM, less variability than NPH
  • Insulin glulisine : Rapidly acting analogue, similar to aspart/lispro
  • Inhaled insulin
  • Oral insulin
slide58
胰島素治療的適應症
  • 第 1 型糖尿病患者。
  • 第 2 型糖尿病患者,空腹血糖超過 300 mg/dL 和合併酮酸血症或酮酸尿症。
  • 第 2 型糖尿病患者,持續性出現空腹血糖超過 300 mg/dL 和出現多尿、多喝及體重減輕的症狀。
  • 願意接受胰島素做為第一線治療的患者。
  • 妊娠型糖尿病患者無法以飲食控制者。
  • 第 2 型糖尿病婦女懷孕時。
slide59
胰島素合併口服抗糖尿病藥治療(1)

一般而言,此種情形是使用中效胰島素,於睡前注射,使空腹能維持於理想範圍內。它的好處在於:

  • 容易衛教。
  • 門診時容易使用。
  • 病患配合度高。
  • 心理調適容易。
  • 較少胰島素劑量。
slide60
胰島素治療:每日兩次注射胰島素 (2)

以一天注射兩次(早餐前、晚餐前)為例,這種方式目前最常使用於第 2 型糖尿病的病患和第 1 型糖尿病的幼童。

  • 計算劑量:一般建議,身體質量指數小於 25 kg/m2者,以每公斤 0.4 至 0.6 單位計算起始劑量;而體重超過 25 kg/m2者以 0.6 至 1.0 單位計算。
  • 劑量調整:需要根據相對應的血糖來調整胰島素劑量。
slide61
胰島素治療:多次注射胰島素 (3)

每日早晚兩次注射胰島素時,有些人發現清晨空腹血糖居高不下,這時不妨晚餐前只注射短效胰島素,把中效胰島素移到睡前注射。第 1 型糖尿病病患,如果每日注射兩次,可能會出現午餐後血糖偏高,此時需要午餐前注射短效胰島素。對於多數第 1 型糖尿病病患和晚期第 2 型糖尿病病患而言,比較接近生理需求的注射方法可能是睡前注射中效胰島素來滿足基本需要量,白天每餐前半小時注射短效胰島素。

slide62
胰島素治療:連續性皮下胰島素輸注 (4)
  • 連續性皮下胰島素輸注:利用幫浦,將裝置在注射筒內的胰島素,以軟管和注射針頭連接後置入皮下組織,並將注射針頭固定於皮下組織以提供胰島素連續注射的一種方法。
  • 胰島素幫浦能夠達到良好控制病患血糖的目的。
  • 開始劑量常用原來每日總量的 40-60%,一半作為基礎量胰島素,另一半則作為追加量胰島素。
slide63
胰島素治療:連續性皮下胰島素輸注 (4)

優點:

  • 注射一次可維持 3 天。
  • 改進血糖的控制。
  • 飲食、運動及作息較具彈性。
  • 減少嚴重低血糖的發生。
  • 發生低血糖時較易處理。
slide64
胰島素治療:連續性皮下胰島素輸注 (4)

缺點:

  • 幫浦機器。
  • 機械故障、輸注管阻塞。
  • 發炎或感染。
  • 酮酸血症。
  • 花費昂貴。
slide65
胰島素治療的優點與缺點

(一)胰島素治療的優點:

(1)對口服抗糖尿病藥無效的病人,可以

迅速改善血糖的控制。

(二)胰島素治療的缺點:

(1)低血糖。

(2)體重增加。

(3)配合度差。

slide66
結語
  • 血糖濃度越接近正常範圍,越容易發生嚴重的低血糖。因此越需要加強血糖自我監測,營養及護理衛教。
  • 速效及長效胰島素類似物的出現,讓我們能以更接近正常生理方式控制血糖。
  • 多次注射胰島素能夠達到良好控制病患血糖的目的。