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1 2006 년분당서울대병원내과연수강좌 증례를중심으로한 인슐린치료 분당서울대병원내과 장학철 2006 년 8 월 27 일

2 Insulin Therapy in Type 2 Diabetes Insulin-Requiring Diabetes: A Pathophysiologic Perspective Treating Diabetes with Insulin: Restoring Normal Patterns Case Studies

3 Insulin resistance and β-cell dysfunction are core defects of type 2 diabetes Genetic susceptibility, obesity, Western lifestyle Insulin resistance IR β β-cell dysfunction Type 2 diabetes Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3 13.

4 More than 80% of patients progressing to type 2 diabetes are insulin resistant Insulin sensitive; low insulin secretion (16%) Insulin sensitive; good insulin secretion (1%) Insulin resistant; low insulin secretion (54%) 83% Insulin resistant; good insulin secretion (29%) Haffner SM, et al. Circulation 2000; 101:

5 9 Gradual loss of glycemic control occurs despite various oral agents HbA 1c (%) 8 7 Conventional therapy (primarily diet alone*) Glyburide Chlorpropamide Metformin Time from randomisation (years) ULN = 6.2% *Therapy assigned if FPG > 15 mmol/l or symptoms of hyperglycaemia Overweight patients Cohort, median values Adapted from UKPDS Group. UKPDS 34. Lancet 1998; 352:

6 The UKPDS demonstrated progressive decline of β-cell function over time 100 β-cell functi ion (% β) Mean β-cell function at diagnosis Start of treatment p< HOMA model, diet-treated n = 376 Time (years) Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl): S21 5.

7 Potential benefits of the addition of insulin therapy in type 2DM before β-cell failure Induce long-term optimal glycemic control approaching HbA1c <7% Reverse glucotoxicity and preserve β-cell function Improve insulin sensitivity in peripheral tissue and reverse insulin resistance Restore postprandial insulin response and improve basal insulin levels to near-normal Spare β-cells and preserve β-cell function Suppress basal hepatic glucose production Enhance subsequent response of β-cells to oral agents therapy Prevent development of microvascular complications

8 Normal Plasma Insulin Profile Plasma levels Endogenous insulin Breakfast Lunch Dinner Time of day Adapted from McCall AL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc; 2002:

9 Milestones in Diabetes Treatment Insulin discovered NPH insulin First sulphonylureas Lente insulins Metformin A1C Insulin pump DCCT Pen Type UKPDS Rapid-acting insulin Analogue Long Acting Insulin Analogue DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study. 1. US FDA Center for Drug Evaluation and Research. Available at: Accessed March 18, Lantus Consumer Information. Available at: Accessed March 18, 2003.

10 Human Insulins vs Analogues Insulin Onset of Peak of Preparations Action Action Duration of Action Short-acting RHI min 2-4 h 6-8 h Lispro 1,2 15 min 1-2 h 2-5 h Aspart 1, min 1-3 h 3-5 h Insulin glulisine min 1-2 h 3-4 h Intermediate-acting NPH h 5-7 h h Lente 1 1-3h 4-8 h h Long-acting Glargine h Peakless ~24 h Detemir 3-4 h 6-8 h 23 h Ultralente h 8-14 h <20 h Pre-mixed Insulin lispro 75/25 *10 10 min 1-4 h h Insulin aspart 10 min 1-4 h h 70/30 10 *75% insulin lispro protamine suspension/25% insulin lispro. 70% intermediate-acting protaminated insulin aspart/30% rapid-acting soluble insulin aspart. RHI=regular human insulin; NPH=neutral protamine Hagedorn.

11 ADA, AACE,IDF and KDA glycemic goals Biochemical index ADA 1,2 AACE 3 IDF 4 (Global) HbA 1c (%) < 7 < 6.5 < 6.5 KDA 5 < 6.5 mg/dl mg/dl mg/dl mg/dl Fasting/preprandial plasma glucose < 110 < 110 Postprandial plasma glucose < 180 < 140 NA Bedtime plasma glucose NA NA 1 American Diabetes Association. Diabetes Care 2004; 27:S15 S35. 2 American Diabetes Association. Diabetes Care 2002; 25:S35 S49. 3 American Association of Clinical Endocrinologists. Endocrine Pract 2002; 8 (Suppl. 1): Korean Diabetes Association 2005

12 Case Study Temporary Insulin Therapy: diabetic foot Temporary Insulin Therapy: minor surgery Type 1 Diabetes Type 1 Diabetes, Poor control Type 2 Diabetes, Salesman Type 2 Diabetes, Poor control

13 Temporary Insulin Therapy: Infection 52 y/o man currently being treated with gliclazide mg and metformin 500 mg bid Type 2 diabetes, well-controlled prior to onset of diabetic foot Develops ulcer of left foot A1c= 7.4%, SMBG; pre-prandial BG: mg/dl Antibiotics begun as outpatient treatment You increase the metformin to 1000 mg bid without improvement in the blood glucose after 7 days.

14 Temporary Insulin Therapy Points to Consider Glucose levels increase with stress of infection Glucose levels increase when unable to exercise With increased insulin resistance and infection, insulin secretagogues and metformin are often inadequate WBC s become dysfunctional at glucose levels greater than 160 mg/dl Must consider alternative treatment

15 Temporary Insulin Therapy Treatment Choices Add insulin glargine at 10PM Add insulin glargine with supplemental RA insulin NPH as insulin stage 2 Mixed split as insulin stage 2 Premixed insulin as insulin stage 2

16 Temporary Insulin Therapy Decision points Imperative to gain control of glucose to successively treat infection Need physiological insulin supplementation Education for self-injection If treatment of infection is successful, insulin therapy may be temporary Target glucose levels: mg/dl (premeal)

17 Temporary Insulin Therapy Option Start insulin glargine at 10PM; supplement with insulin lispro/aspart if needed Insulin glargine 10 U, add 2U q 2-3 days until FBG within target Supplement lispro/aspart 2 U for premeal glucose > 150 mg/dl, then add 1U/ 50 mg/dl > 200 mg/dl Use mealtime insulin as pattern dictates

18 Temporary Insulin Therapy After the first 14 days the glargine dose was increased to 22 U Average glucose levels: Add 4 U RA insulin before supper

19 Temporary Insulin Therapy Summary Temporary insulin therapy is often required, especially for well-controlled patients with type 2 diabetes with infections There are several options for different insulin regimens to use Insulin requirements will change, so frequent glucose monitoring will be required Temporary insulin therapy is an excellent way to introduce patients to insulin and can subsequently be used for future brief illnesses

20 Temporary Insulin Therapy Treatment Choices Add insulin glargine at 10PM Add insulin glargine with supplemental RA insulin NPH as insulin stage 2 Mixed split as insulin stage 2 Premixed insulin as insulin stage 2

21 Temporary Insulin Therapy: minor surgery 63 y/o man currently being treated with glimepride 4 mg bid, RSG 4 mg qd and metformin 500 mg bid Type 2 diabetes for 16 yrs, borderline-controlled Scheduled to angioplasty for ASO 174 cm, 75 kg, BMI = 24.8 A1c= 7.7%, FPG: 160 mg/dl Diet pattern: irregular, snack

22 Temporary Insulin Therapy Option Start premixed insulin Novomix twice daily Stop GMP and RSG Novomix 20 U at breakfast and 10U at dinner DM education for insulin injection Survival skill & MNT

23 Temporary Insulin Therapy After the first 4 weeks the Novomix dose was increased to 32 U -16 U Average glucose levels: After 3 Mo, A1c = 6.3%

24 Type 1 Diabetes 35 yrs woman, T1DM 13yrs Visit ER d/t generalized edema, fatigue Diagnosed as DKA Current insulin : mixed split insulin (stage 2) 163 cm, 52.3Kg, ideal BW:55.8Kg, BMI:20 Lab data : RG 152, BUN 5, Cr 0.6, TC 205, TG 194 Pro 6.0, Alb 3.0, Hb/Hct 12.7/41.1, HbA1c 15.9%

25 Type 1 Diabetes Starting MSII Total daily insulin dose: 55 x 0.6 = 34 U Basal insulin dose: 18 U Initial dose of glargine: 0.8 x 18 = 15 U Diet education: 0.8 g protein/kg Carbohydrate counting Initial HL dose: 4 U for B depending meal size, 6 U with L, and 6 U with D More frequent SMBG

26 Type 1 Diabetes Micro-Cx Microalbuminuria mild NPDR Neuropathy: DPN Insulin regimen Humalog 6/6/8u + Lantus 20u MNT

27 T1 DM, Poor control 42 yrs Man Diagnosed as T2DM 5 yrs ago Initially treated with OHA, but failed to control glucose -> NPH 30U -10U C-pep/ Insulin: <0.1/ 19.1; FBS: 78/267/9.0% NPH(3/7) 32 U/ NPH(3/7) 12U FBS: 147/198/9.3% MSII: HL /NPH 10 FBS:64/ 8.3%

28 T2 DM, salesman 56 yrs men diagnosed with T2DM 16 yrs ago Gliclazide 160 mg bid and metformin 1000 mg bid Mostly sedentary, lost 4 kg for 4 months FBS: /A1c: 9.2% Fenofibrate 160 mg for high TG and low HDL; ARB for HTN

29 T2 DM, salesman Indication for initiating insulin Add TZD? If you choose to begin insulin, what regimen would you select, at what dosage, and how would you titrate the dosage?

30 Indication for initiating insulin Significant, symptomatic hyperglycemia (eg, weight loss, polyuria) Inadequate glycemic control, despite adherence to diet and treatment with maximal doses of OHA Stress (trauma, surgery, infection) Pregnancy Contraindications to OHA

31 Insulin Therapy in T2DM Treatment Choices Combination Tx: Add glargine or NPH at bedtime Insulin dose: U /kg Increase 1-2 U every 2-3 days until FBS < NPH or premixed insulin as insulin stage 2 Add Metformin or TZD

32 T2 DM, Poor control 63 yrs men with T2DM diagnosed at 1981 Alcohol 2/wk, 0.5 B/ Smoking : 0.5 P/day LIPID: /A1c: 8.4% Diet : regular, small sanck Exercise: no regular exercise Medication: GMP 4 mg-1 mg bid; Aspirin protect 100 mg; Thioctacid 600 mg; Metformin 1000 mg bid; Simvastatin 20 mg

33 T2 DM, Poor control FBS/PP2:199/384/8.4% Change to insulin therapy Stage 2 Stop GMP Novomix 26u at 7A, 12u at 5P Novomix 30u at 7A, 14u at 5P After 3 Mo, FBS/PP2: 110/189/7.1%

34 T2 DM, Poor control 69 yrs man with T2DM for 23 yrs and HTN for 10 yrs : A1c: 7.1% Mild NPDR, DPN, microaluminuria Pioglitazone 15 mg + Metformin 850 mg bid + Gliclazide 160 mg bid

35 T2 DM, Poor control C-peptide/ insulin: 2.0/6.6 FBS/PP2:158/ % Change to combination Tx Stop actos and reduce gliclazide 160 mg qd Start Lantus 10 U at 10 PM and adjust according to FBS (Target mg/dl) After 3 mo, Lantus 12 U FBS :116/248/7.4%

36 Insulin Therapy in T2DM Weight gain: 2-6 kg Weight loss prior to insulin Tx Poor control, A1c TZD> Metformin Hypoglycemia Worsening retinopathy

37 Barriers to achieving good glycemic control Lack of clarity over definition of good glycemic control Inadequate monitoring of glycemia Complexity of managing hyperglycemia relative to dyslipidemia and hypertension Insufficient involvement of specialist care units

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract