General Summary of DM, with Medications

(part II, drug therapy) 영양병원 내과 이준엽

Drug Therapy

1. Oral hypoglycemic agent ① Sulfonylurea ② Meglitinide ③ Biguanides ④  -glucosidase inhibitor ⑤ Thiazolidinedione ⑥ Others

–

orlistat, sibutramine 2. Insulin

Action Mechanisms of Oral Hypoglycemic Agents

Relationship between HbA1c and sugar level HbA1c above Mean blood glucose normal level (%) (mg/dl) 1 ∼ 150 2 ∼ 180 3 ∼ 210 4 ∼ 245 5 ∼ 280 6 ∼ 310 7 ∼ 345 8 ∼ 380 9.5 10.0 10.5 11.0 11.5 12.0 13.0 HbA1c 6.5 BG = 135 7.0 7.5 8.0 8.5 9.0 = 150 = 165 = 180 = 195 = 210 = 225 = 240 = 255 = 270 = 285 = 300 = 330

Nathan DM, et al., NEJM 310:341, 1984

Monitoring Parameters for Control of Complications

Every visit Blood Pressure Foot Exam (55% achieve goal) _______________________________________________________ 3-6 months A1C - Every 3 months if treatment changes or not meeting goals - Every 6 months if stable _______________________________________________________ Annual Dilated Eye Examination (63% achieve goal) Lipid Levels* Microalbumin _______________________________________________________ *Every 2 years if levels fall in lower risk categories

Impact of Therapies on A1C Levels

Therapy A1C Reduction       Diet and Exercise Insulin >5.0% 0.5 - 2.0% Sulfonylureas and Glitinides 1.0 - 2.0% Metformin  -Glycosidase Inhibitors Thiazolidinedione 1.0 - 2.0% 0.5 - 1.0 % 0.5- 1.0% Nathan, D. Oct 2002. N Engl J Med, Vol. 347, No.17

Flow Chart by Initial Sugar Level in Type 2 Diabetes (By Staged Diabetes Management) Initial Sugar Level FBS < 180 mg/dl Random < 250 mg/dl Diet & Exercise Oral Agent Initial Sugar Level FBS 180-250 mg/dl Random 250-350 mg/dl Combination Initial Sugar Level FBS > 250 mg/dl Random > 350 mg/dl Insulin

Major target organs and actions of OHAs in Type 2 DM.

TZD = thiazolidinedione; FFA = free fatty acid; AGI =a-glucosidase inhibitor.

Therapeutic Agents for Type 2 Diabetes

Mechanism of Action Agent 1. Sensitize the body to insulin  2. Control hepatic glucose production  Thiazolidinediones, Biguanides Biguanides, Thiazolidnediones 3. Stimulate the pancreas to  Sulfonylureas make more insulin 4. Slow the absorption of starches  Meglitinides Alpha-glucosidase 5. Decreases hepatic glucose  inhibitors Insulin production and increases peripheral glucose uptake

Sulfonylureas

• • Increase endogenous insulin secretion Efficacy - decrease blood glucose ~ 60 - reduce HbA1c 1.0 - 2.0

% mg/dl - no specific effect on plasma lipids or blood pressure Other Effects - hypoglycemia - weight gain

Sulfonylureas

Characteristics of sulfonylurea

Approved Daily Duration of Generic name Dosage Range, mg Action, h Clearance First generation Chlorpropamide (Diabinase) 100-500 >48 Renal Tolazamide 100-1000 12-24 Hepatic, renal Tolbutamide 500-3000 6-12 Hepatic Second generation Glipizide (Diagreen) Glyburide (Daonil) Gliquidone (glurenorm) 2.5

–

40 12-18 Hepatic 1.25-20 12-24 Hepatic, renal 30-180 12-24 Hepatic Gliclazide (Diamicron) Glimepiride (Amaryl) 80-240 1-8 12-24 Hepatic, renal 24 Hepatic, renal

Indications of Sulfonylurea

1. Onset age > 40 years 2. Onset duration < 5 years 3. Normal weight or obese 4. Never received insulin or controlled < 40U/day

Contraindications of Sulfonylurea

1. Type 1 DM or pancreatic DM 2. Pregnant or lactating women 3. Undergoing surgery 4. Severe infection 5. Severe stress or trauma 6. Severe adverse reaction to sulfonylurea

: Indication of Insulin Therapy

Side Effects of Sulfonylurea

1. Hypoglycemia 2. Weight gain 3. Allergies to sulfonylureas 4. Alcohol intolerance 5. Hyponatremia

Meglitinides

Non-sulfonylurea insulin releasing agent; taken before each meal Rapid onset of action with a duration of action of several hours • • Efficacy - decrease peak postprandial glucose - decrease blood glucose 60 - 70 mg/dl - reduce HbA1c 1.0 - 2.0

% Other Effects - hypoglycemia - weight gain - safe at higher levels of creatinine than sulfonylureas

Glinides

Dose range Peak level Half-life Metabolite (mg/day) (h) (h) excretion Meglitinide repaglinide (Novo norm  ) 1.5-12 0.75 1 inactive bile D-phenylalanine derivative nateglinide 360 1.0 1.4 weakly active (Fastic  ) kidney

Biguanides

Decrease hepatic glucose production and secondarily may increase insulin-mediated peripheral glucose uptake • Efficacy - decrease blood glucose ~ 60 mg/dl - reduce HbA1c 1.0 - 2.0

% - cause small decrease in LDL-C and triglycerides - no specific effect on blood pressure - no weight gain • Other Effects - diarrhea and abdominal discomfort - lactic acidosis if inappropriately prescribed - contraindicated in patients with impaired renal function

Metformin activates AMPK in liver and muscle to improve glucose and lipid metabolism in type 2 diabetes.

Biguanides

• Agent-specific advantage 1) weight loss 2) improve lipid profile 3) no hypoglycemia • Side effects 1) lactic acidosis (1/20,000 Pt.yr) 2) nausea, diarrhea, anorexia

Biguanides

• Contraindications 1) renal insufficiency (s-Cr > 1.4 in women, >1.5 in men) 2) any form of acidosis 3) congestive heart failure 4) severe liver disease

Thiazolidinediones

Potentiate insulin action on muscle and adipose tissue , decrease peripheral insulin resistance • • Efficacy - decrease FPG ~ 25 - 40 mg/dl - reduce HbA1c ~ 0.5 - 1 % (full hypoglycemic potency, until 12 Wks of Tx.) - combined with sulfonylureas reduce HbA1c ~ 0.8 - 1.0

% - combined with insulin reduce HbA1C by 0.8 - 1.4

% - Beneficial effect on lipids - Possible cardiovascular effects Other Effects - contraindicated with abnormal liver function - weight gain, edema

Mechanism of Action(PPAR-



)

DRUG PPAR



RXR retinoic Regulates gene transcription

AGGTCA X AGGTCA

PPRE (DR-1) Gene encoding GLUT-4, lipoprotein lipase, PEPCK etc.

Mechanism of action of Thiazolidinediones.

Thiazolidinediones

• Side Effects 1) hepatotoxicity (AST/ALT, BIL MONTHLY FOR THE FIRST 8 MONTHS, EVER 2 MONTHS FOR THE FIRST YR) 2) minor weight gain(1-2kg) 3) peripheral edema • Contraindications 1) liver disease 2) congestive heart failure (class III or IV)

Alpha-Glucosidase Inhibitors

Competitive inhibitor of alpha glucosidase enzymes in small intestines; taken before meals • • Efficacy - decrease fasting plasma glucose 20-30 mg/dl - decrease peak postprandial glucose 40-50 mg/dl - no specific effect on lipids or blood pressure - reduce HbA1c 0.5-1.0

% Other Effects - abdominal discomfort and flatulence - contraindicated with inflammatory bowel disease or cirrhosis

Alpha-Glucosidase Inhibitors

• Side effects diarrhea, flatulence, abdominal distension, hepatotoxicity • Contraindication 1) inflammatory bowel disease 2) gastroparesis 3) s-Cr > 2.0 mg/dl

Anticipated Response to Treatment

Agent Time to Response Secretatogogues Long-acting Rapid-acting 7 – 10 days Immediate SMBG Indicator Fasting Postprandial Metformin Glitazones AGIs Insulin Rapid Acting Long-acting 2 – 3 weeks 6 – 8 weeks Immediate Immediate Immediate Fasting Postprandial Postprandial Fasting

아마릴

2 m g (

한독약품

)

아마릴

1 m g (

한독약품

)

다오닐

(

한독약품

)

다오닐 세미

(

한독약품

)

디아미크롱

(

한화약품

)

글리클라짓

(

삼천당제약

)

디베린

(

코오롱제약

)

유글루콘

(

종근당

)

다이아비네스

(

한국화이자

)

글루레노름

(

한국베링거인겔하임

)

다이그린

(

유한양행

)

굴루코파지

(

대웅제약

)

글루코바이

(

한국바이엘

)

베이슨

(

제일제당

)

Oral Hypoglycemic Agents

* 혈당강하 효과 인슐린 분비촉진제, 메트포르민, TZD: 1-2% 알파-글루코시다제 억제제: 0.5-1% * 작용시간 빠른효과: 인슐린 분비촉진제, 알파-글루코시다제 억제제 늦은효과: 메트포르민, TZD * 저혈당이 없는 약제 메트포르민, TZD, 알파-글루코시다제 억제제

동반질환에 따른 약물의 선택

신기능(mg/dL) 간기능 <1.4 1.4~2.0 >2.0

Sulfonylurea Meglitinide Biguanide  -GI TZD Insulin

병합약제의 선택

현재 치 료제 추가 설폰요소제 • 메트포르민 • 치아졸리딘디온 • 알파 글루코시데이즈 억제제 메트포르민 • 설폰요소제 • 레파-, 나테글리나이드 • 치아졸리딘디온 • 알파-글루코시데이즈 억제제 • 인슐린 알파-글루코시데이즈 억 제제 • 설폰요소제 • 메트포르민 • 인슐린 현재 치 료제 추가 치아졸리딘디온 • 설폰요소제 • 메트포르민 • 인슐린 레파-, 나테글리나이드 • 메트포르민 설폰요소제 + 글리나이드 알파글루코시다제 억제제+글리나이드

병합약제의 선택(보험)

설폰요소제, 메트포르민, 알파-글루코시다제 억제 제 글리나이드 : 단독 또는 메트포르민 병합, 3제병합, 인슐린병합 불인정 TZD: 설폰요소제 또는 메트포르민 병합, 인슐린 40단위 이상 사용자 단독요법 (2008년개정, 제외됨), 3제병합 불인정 예) Amaryl 2T, Metfromin 2T, Avandia 1T

Insulin

Decreases hepatic glucose production and increases uptake and use of glucose by muscle and adipose tissue • Efficacy - can lower plasma glucose to any level - reduces HbA1c > 5.0

% - limited by hypoglycemia • Other Effects - hypoglycemia - weight gain

기저인슐린(basal ) vs 식사인슐린(bolus) • 기저인슐린 (basal insulin) – 간 포도당 생성억제 – 하루 요구량의 40 -50% • 식사인슐린(bolus insulin) – 식후고혈당 조절 – Immediate rise and sharp peak at 1 hour – 매 식사마다 하루 요구량의 10 20%

인슐린제제의 종류 및 작용시간

Onset of action, peak, and duration of action of exogenous insulin preparations.

(Neutral protamine Hagedorn = NPH)

인슐린 치료의 적응증

• 진단시 심한 고혈당 • 혈당조절 목표 도달(to meet glycemicgoals) • 경구용 약물요법 실패 • 급성 대사성 합병증(DKA / NKHS) • 동반 질환이 있는 경우: 감염, 수술, 간/신 장질환 • 심한 체중감소 • 임신

인슐린 치료 시작 지침

• 사용중인 경구용 약제를 계속 사용한다. (예; 메트포르민) • 중간형 또는 지속형 인슐린을 취침 전에 투여한다.

• 초기 인슐린 용량은 10 unit 또는 0.1 -0.2 u/kg로 한다.

• 공복혈당을 측정해서 70-130 mg/dl로 유지한다.

• 공복혈당이 목표치에 도달하도록 3일 간격으로 2-4 단위씩 증량한다.

인슐린 용량 조절

• 최소3 - 4일 간격으로 서서히 증량한다.

• 저혈당을 우선 교정한다.

• 한번에 1회 인슐린 용량만 조정하고 모든 혈당이 200 mg/dl 이상인 경우에는 0.1 U/kg의 인슐린 을 추가한 후 나누어 증량한다.

• 하루 총 인슐린 요구량이 1.5 U/kg 이상이면 인 슐린 감작제의 추가를 고려한다.

• 하루 종일 고혈당이 계속되면 가장 높은 혈당부 터 교정하고, 모든 혈당이 50mg/dl 이하이면 아 침 혈당부터 교정한다.

인슐린 용량 조절

The Incretin Effect Demonstrates the Response to Oral vs IV Glucose • Insulin Secretions : Oral > IV glucose

Schematic drawing of the role of DPP-IV in the inactivation of incretins (GLP-1, GIP, PACAP) (see text). DPP-IV-truncated GLP-1 and GIP act as weak receptor antagonists

The Incretin Effect Is Reduced in Pts. With T2DM

GLP-1 Key Regulating Peptide in Glucose Metabolism

혈당 조절의 실제

• Type 2 DM 특징 1) 인슐린저항성이 병인 2) 식후 고혈당이 흔함.

경구약제 단독요법 경구약제 선택 경구약제 시작 용량 투여 평가 경과 관찰 1주 목표에 도달 아니오 예 유지 용량 지속 증량 2 - 4주 (4 - 8 주:  -GI*, 8 - 12 주: TZD**) 동안 최대 용량 사용 후 목표에 도달하지 못함 다른 경구약제/병합요법/혹은 인슐린 요법

경구약제 병합요법 경구약제 단계에서 현재 사용중인 약제로 목표에 도달하지 못함 현재 사용중인 경구약제의 용량을 유지하고 다른 경구 약제의 초회 시작 용량을 추가 아니오 경과 관찰 1-2주: 목표 도달 아니오 증량 예 유지용량 지속 최대 용량까지 증량하여 8 12주 이상 사용하였는가?

3개월 동안 목표에 도달 못함 다른 병합요법/인슐린 요법

Profile of ideal insulin replacement pattern.

당뇨조절의 실제

Breakfast Lunch Dinner

AGI

4:00 8:00 12:00 16:00 20:00 24:00 4:00