Diabetes

충남대학교병원 약제부 박현정

Glucose regulation

1. Insulin is the principle hormone regulating glucose

- discovered in 1921

2. Functions

- Promote glucose uptake by cells

: glycogenesis, triglyceride synthesis

- Prevent fat & glycogen breakdown,

promote TG synthesis from FFA

- Increase protein synthesis/ inhibit protein breakdown

3. Insulin is synthesized in pancreatic β-cell

Other hormones affecting blood glucose:counter-regulatory hormones

1. Catecholamines

2. Growth hormones

3. Glucocorticoid hormones

Etiologic factors associated with DM

• Obesity• Increasing age• Heredity• Emotional stress• Autoimmune response• Endocrine diseases (Cushing’s disease)• Viral infection• Insulin receptor or post-insulin receptor defect• Drugs

Drugs that may alter blood glucose levels

• Corticosteroids• Diazoxide• Phenytoin• Caffeine• Thyroid hormones• Oral contraceptives• Epinephrine-like agents• Lmmunosuppressants• Atypical antipsychotics• Thiazide diuretics

Diabetes Mellitus

1. Disorder of carbohydrate, protein and fat metabolism resulting form an imbalance between insulin availability and insulin need

2. ClassificationTypes casusesType 1(IDDM) β-cell destruction, lack of insulinType 2 (NIDDM) Insulin resistance, insulin deficiencyOther specific types Genetic defects in β-cell function pancreas diseases (exocrine and endocrine diseases), infection, drug/chemical-induced, immune-mediatedGestational(GDM) Insulin resistance with impaired insulin secretion

Type 1 diabetes

1. β-cell destruction leading to insulin deficiency

: absence of insulin and high levels of glucagon.

2. Autoimmune disease.

: Autoantibodies to insulin, GAD and ICA512

: 90-95% in Caucasians

: 50% in Koreans

3. Patients with Type 1 diabetes are lean

4. It can be developed in youth or young adulthood.

5. Tx : Insulin administration

Type 2 diabetes

1. Type 2 diabetes is a disease that generally develops

over a period of years.

2. impaired insulin secretion from the pancreas and insulin resistance.

3. Insulin resistance initially stimulate insulin secretion

: eventual exhaustion of beta cells

4. Patients with type 2 diabetes are less prone to

ketoacidosis.

Type 2 diabetes

5. 80% of patients with type 2 diabetes are overweight.

6. It has a strong genetic basis although the genes have not

yet been identified

7. Environmental factors, such as obesity, a high-fat diet,

physical inactivity, or some medications

8. Insulin resistance syndrome, syndrome X, metabolic syndrome

: high levels of blood glucose, triglycerides, low levels of HDL, hypertension, coronary heart disease

9. Tx : Lifestyle modification

Oral medication

Insulin administration

Typical Clinical Presentation of Diabetes Mellitus

Characteristic Type 1 Type2Age of onset Childhood or adolescence Greater than 40 years of age

Onset Abrupt Gradual

Family history Negative Positve

Body type Thin Obese or history of obesity

Metabolic syndrome No Often

Autoantibody Present Rare

Symptoms Polyuria, polydipsia, Asymptomatic

polyphagia, rapid weight loss

Ketones at diagnosis Present Uncommon

Acute complication Diabetic ketoacidosis Rare

Microvascular Rare Common

complication at diagnosis

Macrovascular Rare Common

complication at diagnosis

Symptoms of diabetes

In type 1 diabetes, symptoms arise suddenly,

however type 2 diabetes is often without symptoms

in its early stages

• polyuria, polydipsia, polyphagia

• feeling tired and weak

• weight-loss :loss of body fluid, loss of body fat and proteins

• having frequent infections

• having blurred eyesight

Diagnosis

1. Fasting plasma glucose : FPG ( ＞ 126mg/dL ) Fasting: no caloric intake for at least 8hr 정상치 : FPG ＜ 109mg/dL 2. Random (Causal) plasma glucose : RPG ( ＞ 200mg/dL ) Causal: any time of day without regard to time since last meal3. Oral glucose tolerance test ( OGTT ) 75g glucose loading 후 2hr plasma glucose : ( ≥ 200mg/dL ) 정상치 : 2hr PG ＜ 139mg/dL 4. Glycosylated hemoglobin( HbA1c ) : index of blood glucose level during the previous 2~3 months ( 8% ) 정상치 : 4~6% 1% 상승시 혈당 30mg/dL 상승 의미 Long-term complication 의 primary pridictor

Diagnosis

5. Gestational diabetes mellitus ( GDM )

≥ 95mg/dL Fasting, ≥ 180mg/dL at 1hr

≥ 155mg/dL at 2hr , ≥ 140mg/dL at 3hr

6. SMBG ( Self Monitoring Blood Glucose )

: 모세혈관 전혈을 이용하여 혈당 측정 ( 혈장보다 10~15% 낮게 측정 )

: 목표 SMBG fasting 80 ~ 120mg/dL

postprandial (2hr) ＜ 160mg/dL

bedtime 100 ~160mg/dL

Acute Complications

Insulin insufficiency

1. Diabetic Keto-acidosis (DKA) : hyperglycemia, low bicarbonate, low pH, Ketonemia, ketonuria : osmotic diuresis, dehydration, loss of electrolytes

2. Hyperosmolar non-ketotic Coma (HONK) Hyperglycemic hyperosmolar nonketotic syndrome (HHNK) : dehydration, neurologic signs, thirst, thromboembolic events ＞ 600mg/Dl

3. Somogyi effect : insulin-induced hypoglycemia can produce a compensatory increase in blood catecholamines, glucagon, cortisol and growth hormone

Acute Complications

Insulin excess1. Hypoglycemia - mild ( BG ＜ 70mg/dL ) : 발한 , 빈맥 , 두통 , 시야장애 , 공복감 , 어지러움 - moderate ( BG ＜ 50mg/ dL ) : 사고력 장애 , 집중력 소실 , 복시 , 착란 , 운동실조 , 졸림 등 - severe ( BG !! ) : 의식소실 , 경련 , 혼수 - 원인 : 과량의 insulin or oral hypoglycemic agent 음식섭취 감소 , 포도당 이용 증가 ( 운동 등 ), 인슐린 제거율 감소 ( 신 / 간기능 부전 ) - 치료 : 15~20g glucose, severe- glucagon IM - self management : BG ＜ 70mg/dL 15g glucose 섭취 15g glucose: 꿀 한숟가락 , 오렌지쥬스 1 컵 , 요구르트 1 개 , 사탕 3~4 개 , 콜라 ½ 캔

Chronic Complications

1. Microvascular disorder 1) Eyes - Retinopathy: abnormal retinal vascular permeability, neovascularization, hemo

rrhage, scarring, retinal detachment - Impaired vision blindness 2) Kidneys - Diabetic nephropathy - Renal failure, transplantation - Microalbuminuria is the first manifestation of nephropathy 3) Nerves - Neuropathy: demyelinating effect - Pain, loss of sensation

Chronic Complications

4) Peripheral circulation

- lmpaired healing, poor blood flow

- lesions, infections

5) Diabetic foot ulcer: neuropathy, skin change, poor

circulation

2. Macrovascular disorder

- Uncontrolled blood glucose + elevated BP + hyperlipidemia

- Hypertension

- Coronary Artery Disease

- Cerebrovascular (strokes)

당뇨병성 신증의 발생과 자연경과

당뇨병 발생 0 ~ 5 년 : 조기 신기능 부전11 ~ 23 년 : 단백뇨 발생13 ~ 25 년 : 신기능 부전18 ~ 30 년 : 말기 신부전증

잠복성 신증의 예측 인자 : 미세 알부민뇨 , 혈압증가

Type 1 DM : 35% 에서 당뇨병성 신증 발생Type 2 DM : 15~60% 에서 당뇨병성 신증 발생

Insulin

Indication

절대적 적응 ( 인슐린 치료를 하지 않으면 생명이 위급한 경우 )

- Type 1 (IDDM)

- DKA & HONK

- GDM

- Acute physical stress ( Infection, Injury, Surgery )

상대적 적응 - NIDDM 에서 식사요법 / 운동요법 / 경구용 혈당강하제로 치료해도 혈당조절이 충분치 않을때 - 간질환 및 심기능 저하가 동반되어 경구용 혈당강하제를 사용할수 없을때 - 다른 질환의 치료를 위해 Corticosteroid 를 투여하여 혈당조절이 충분하지 않을때

Insulin

1. Rapid acting Insulin ( 초속효성 )

- Onset : 0 ~ 0.25 hr , 식전 15 분내 SC

- Peak : 1 ~ 2 hr

- Duration : 2~ 4 hr

- 종류 : Lispro ( Humalog ), Aspart ( Novorapid ), Glulisine ( Apidra )

2. Short acting Insulin ( 속효성 )

- Onset : 0.5 ~ I hr , 식전 30 분내 SC, IM, IV 가능 - Peak : 2 ~ 4hr

- Duration : 6 ~ 8 hr

- 종류 : Regular ( Humulin R, Novolin R )

3. Intermediate acting Insulin ( 중간형 )

- Onset : 1 ~ 4 hr , 식전 30 분내 SC

- Peak : 4 ~ 6 hr

- Duration : 8 ~ 12 hr

- 종류 : Neutral protamine Hagedone ( Humulin N, Novolin N )

Insulin

4. Long acting Insulin ( 기저형 )

- Onset : 4 ~ 5 hr , 1 일 1 회 환자에 따라 정해진 시간에 SC - Peak : flat

- Duration : 24 hr

- 종류 : Glargine ( Lantus ), Detemir ( Levemir )

5. Combination Insulin product ( 혼합형 )

- 종류 : Humulin NR 70/30

Humalog Mix 25 pen ( Lispro 25%/ Lispro protamine 75% )

Novo Mix 30 Flex pen ( Aspart 30%/ Aspart protamine 70% )

6. Oral inhalation Insulin ( 흡입형 )

- Onset : 10 ~ 20 min

- Peak : 0.5 ~ 1.5 hr

- Duration : 6 hr

- 종류 : ( Exubera ) 1mg, 3mg blister packs

1mg = 3IU injectible insulin

Insulin

※ 제형 : 1000IU/10mi/Vial, 300IU/3ml/Syringe

용량 : 4 ~ 100IU/day

식후 인슐린 요구량 : 4~6IU/hr

기저 인슐린 요구량 : 1~2IU/hr

※ Insulin Pump ( CSII: Continuous subcutaneous insulin injection )

Non-Insulin injectable agent

1. 작용기전 - incretin mimetic agent that mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycemic actions of incretins. Incretins, such as glucagon-like peptide-1 (GLP-1),

2. 종류 : Pramlintide ( Symlin ) Exenatide ( Byetta )

3. ADR: Nausea, Vomitting, diarrhea

4. Precaution: take just before morning and evening meal

prefilled disposable pen ( SC )

may delay absoption of oral drugs: 1hr 사이로 투여

Oral hypoglycemic agent

1. α - Glucosidase inhibitors

2. Sulfonylureas

3. Meglitinides (Glinides)

4. Biguanides

5. Thiazolidinediones

6. Dipeptidyl peptidase -4 inhibitors

α - Glucosidase inhibitors1. 작용기전 - Competitive & reversible inhibition of intestinal α -glucosidase hydrolase & pancreatic α- amlyase : delayed carbohydate metabolism & absorption - 3 times a day just before meals - 식후의 급격한 혈당 상승 감소 - 당질 섭취가 많은 환자에게 효과적

2, Indication: Type 2 DM, Dyslipidemia, Obesity

3. 종류 : Acarbose, Voglibose, Miglitol 4. ADR: Gl symptoms ( flatulence, cramps, abdominal distension ) ↑ LFT ( AST/ALT ), Decreased iron absorption

5. Contraindication: 임산부 , 수유부 , 어린이 , 간경화증 , 염증성 장질환 등

6. 식후고혈당 , 체중증가 및 저혈당 없음 , 효과는 제한적 ,

2nd-Sulfonylureas

1. 작용기전 - Stimulates release of insulin from pancreatic β- cell - increase insulin receptor/ receptor sensitivity

2. Indication: Type 2 DM, BMI ＜ 25kg/m2 FPG ＞ 20mg/dL than treatment goal

3. 종류 : Glibeclamide, Gliclazide, Glimepiride(3rd)

4. ADR: Hypoglycemia, Weight gain, GI disturbance, blood dyscrasias, chloestatic jaundice, ↑ LFT

5. Contraindication: 임산부 , 수유부 , 어린이 , diabetic ketoacidosis 심한 감염증 , 수술 , 간질환 / 신기능 장애 환자

6. 비만하지 않은 환자 , 초기단계 최초 치료 , 1 일 1 회 복용 , 저가 , 저혈당 , 체중증가

Meglitinides (Glinides)

1. 작용기전 - Increases insulin secretion by the pancreas “ Sulfonylurea-like “ - rapid onset and shorter duration than SU - Less effective in decrasing FPG and HbA1c than SU

2. Indication: Type 2 DM , BMI ＜ 25kg/m2, FPG ＞ 20mg/dL than treatment goal high PPG 200~300mg/dL, 불규칙한 식습관 가진 환자

3. 종류 : Repaglinide ,Nateglinide

4. ADR: Hypoglycemia, Weight gain, GI effects, 상기도 감염 , 두통 , 관절통

5. Contraindication: 임산부 , 수유부 , 어린이 , diabetic ketoacidosis 심한 감염증 , 수술 , 간기능 장애 환자

6. Precaution: Frequency of dosing dependent on frequency of meals Side effect reduced risk due to short duration of action7. SU 보다 저혈당 적음 , 고가 , 1 일 3 회 , 체중증가 ,

Biguanides

1. 작용기전 - Decreases hepatic glucose production - Increases peripheral insulin sensitivity - Not stimulate pancreas to release insulin : dose not cause hypoglycemia even in large doses - Increase glycolysis via anaerobic pathway (lactic acidosis) - Cause small decrease in LDL, TG, total cholesterol - 장에서 당흡수 억제

2. Indication: Type 2 DM failed on diet-insulin resistance, Dyslipidemia, Obesity (BMI ≥25kg/m2) FPG ＞ 20mg/dL than treatment goal ( Type 1, 2 DM, Sulfonylurea 계 단독요법에 반응안할때 병용 치료 시작시 혈당이 높을수록 or 비만한 당뇨환자에게

효과적 )

3. 종류 : Metformin

Biguanides

4. ADR: Weight loss, GI symptoms( nausea, diarrhea ), megaloblastic anemia, Lactic acidosis, dysgeusia( metabolic taste)

5. Contraindication: 임산부 , 수유부 , 어린이 고령 ( ＞ 80 years old ), monitor renal function ( 100% renally excreted unmetabolized, discontinue 여 Scr ＞ 1.4mg/dL 남 Scr ＞ 1.5mg/dL ) Radiographic contrast media 병용 Hepatic/renal impairment Past history of Lactic acidosis, CHF 알콜중독자

6. 비만 , 인슐린 저항성 , 이상지혈증 , 위장관부작용

Thiazolidinediones

1. 작용기전 - Increases skeletal muscle cell sensitivity to insulin

- Decreases hepatic glucose production, decreases free fatty acids

- 혈액중의 당대사 촉진

2. Indication: Type 2 DM failed on diet-insulin resistance,

Dyslipidemia, Obesity (BMI ≥25kg/m2)

FPG ＞ 20mg/dL than treatment goal

Metformin 금기시 , 신기능 장애시 사용가능

3. 종류 : Rosiglitazone, Pioglitazone

Thiazolidinediones

3. ADR: Hepatotoxicity ( 사용시작 1 년간 2 개월마다 간기능 검사 )

Monitor LFTs ( ALT 3 배 이상 증가시 투여중단 )

Weight gain, edema, fluid retension, anemia,

Positive effect on lipid profile

( Pioglitazone: ↑HDL, ↓TG, Rosiglitazone: ↑HDL, TG, LDL )

4. Contraindication:Precaution:

임산부 , 수유부 , 어린이 Liver dysfunction

CHF

5. Precaution: Use caution in patients prone to or with heart failure

6. 인슐린 저항성 , Metformin 부적합 신기능 장애시 사용가능 , 저혈당 없음 ,

HDL, TG 개선 , 체중증가 , 부종 , LDL 증가 , 장기간 outcome unknown

Dipeptidyl peptidase -4 inhibitors

1. 작용기전 - Selective & reversible DPP-4 inhibitors - DPP-4 : GLP-1 ( Glucagon-like polypeptide-1 ) 의 분해효소 - GLP-1 : 위장관으로 섭취된 포도당에 자극되어 위벽에서 혈중으로 분비되는 내인성 호르몬 Stimulates release of insulin from pancreatic β- cell inhibition of glucagon from panceratic α-cell - Type 2 DM,

2. 종류 : Vildagliptin , Sitagliptin

3. ADR: Hypoglycemia, Nasopharyngitis, upper respiratory infection Anaphylaxis, Angioedema

4. Precaution: Type 1 DM, diabetic ketoacidosis renal faliure dose adjustment

Glycemic control algorithm for Type 2 DM

1. Diagnosis and initial intervention

- initial FPG ＞ 260mg/dL : Insulin therapy

- initial FPG ≥210mg/dL or HbA1c ≥9.0% : dual oral agent therapy

- Education/nutrition/exercise

2. Target met : HbA1c every 3~6months

- Targets : HbA1c ≤ 6.5 ~7.0%

FPG/SMBG ≤ 110 ~ 130mg/dL

2hr PPG/SMBG ≤ 140 ~ 180mg/dL

3. Target not met after 1 month

- initial monotherapy ( or early dual therapy )

- Sulfonylurea ± metformin

- other oral agent

- insulin

Glycemic control algorithm for Type 2 DM

4. Target met : continue therapy HbA1c every 3~6months

5. Target not met after 3 months

- Sulfonylurea ＋ metformin

- Sulfonylurea or metformin ＋ pioglitazone/rosiglitazone or acabose

- metformin ＋ nateglinide/repaglinide

- insulin

6. Target met : continue combination therapy HbA1c every 3~6months

7. Target not met after 3~6 months

- add bedtime intermediate acting insulin or once daily glargine

before rapid acting insulin (lispro/aspart)

- third oral agent

- switch to split dose insulin

Reference

1. Textbook of Therapeutics : Drug & Disease Management – 제 8 판2. Drug fact & comparisons 20023. Applied Pharmacotherapy4. Lippincott’s Illustrated Reviews: Pharmacology 3rd edition5. Micromedx6. www. Druginfo.co.kr