INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT

INSULIN TREATMENT FOR TYPE 2 DIABETES MANAGEMENT APIRADEE SRIWIJITKAMOL DIVISION OF ENDOCRINOLOGY AND METABOLISM DEPARTMENT OF MEDICINE FACULTY OF MEDICINE SIRIRAJ HOSPITOL

QUESTION 1 1. ท านเคยเป นแพทย คนแรกท เร มให อ นส ล นร กษาในผ เป นเบาหวานท มาตรวจท OPD หร อไม A. YES B. NO

Normal Secretory Pattern of Insulin Total daily insulin requirement = 0.5-1 unit/kg/d Prandial Insulin Insulin Level The 50/50 Rule Basal Insulin Breakfast Lunch Dinner S L E E P

Mrs B 60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg. Currently on Glipizide 20 mg a day Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea) Her last HbA1C 9%, FPG 220 mg/dl

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea) Pioglitazone 30 mg a day Her last HbA1C 9%, FPG 220 mg/dl QUESTION 2 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Lifestyle modification B. Add TZD C. Add AGI D. Add DPP-IV inhibitor E. Add insulin therapy

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea) Pioglitazone 30 mg a day Her last HbA1C 9%, FPG 220 mg/dl QUESTION 3 ถ าท านเล อกจะให อ นส ล นในผ ป วย รายน ท านจะเร มให อย างไร? A. Continue OHA + NPH 6 u B. Continue OHA + NPH 10 u C. Off SU, Cont MET + NPH 10 u D. Continue OHA + Glargine 10 u E. Off OHA + Mix insulin 15 u bid

Oral Hypoglycemic agents failure Add basal insulin

4T Trial STUDY METHOD Glycemic target: A1C 6.5% Basal group Add once (or twice) daily basal insulin* Add prandial insulin if glycaemic target not met 700 T2DM on OAD R Biphasic group Add twice daily biphasic insulin* Add midday prandial insulin if glycaemic target not met Prandial group Add thrice daily prandial insulin* Add basal insulin if glycaemic target not met Randomisation visit One year Two years Three years * progress to more intensive insulin regimen only if clinically necessary stop sulphonylurea if taken Holman RR.N Engl J Med 2009;361:1736

4T Trial EFFICACY % Attainment of Target HbA1c 80 60 40 20 0 HbA1C < 6.5% HbA1C < 7.0% Biphasic group Prandial group Basal group

4T Trial ADVERSE EFFECTS Body weigh gain (kg) %Hypoglycemia (mod to severe) 8 50 6 40 4 30 20 2 10 0 Biphasic Prandial Basal 0 Biphasic Prandial Basal Biphasic group Prandial group Basal group

STARTING WITH BASAL INSULIN ADVANTAGES 1 injection with no mixing Insulin pens for increased acceptance Slow, safe, and simple titration Low dosage Effective improvement in glycemic control Limited weight gain 6-37

BASAL INSULIN Which type? How to start? How to adjust?

TYPE OF BASAL INSULIN NPH insulin Onset: 1 1/ 2 hr Peak: 4-12 hr Duration: 24 hr Insulin Level Long-acting analogue insulin Onset: 2-3 hr Peak: none Duration: 24 hr Intermediate (NPH) Long (Glargine) Hours Long (Detemir) 0 2 4 6 8 10 12 14 16 18 20 22 24

TREAT-TO-TARGET TRIALS Insulin continually titrated to target: Fasting PG 100 mg/dl Insulin glargine once-daily (evening) n = 367 NPH once-daily (evening) n = 389 Insulin detemir twice-daily n = 237 NPH twice-daily n = 238 Riddle et al 2003 Hermansen et al 2006 Insulin continually titrated to target: Fasting and pre-dinner PG 108 mg/dl

Events per patient per year (%) Events per patient per year TREAT TO TARGET HbA 1c 9.0 8.5 NPH + OAD Glargine + OAD 8.0 7.5 7.0 6.5 0 4 8 12 16 20 24 9.0 Weeks NPH + OAD 8.5 Detemir + OAD 8.0 7.5 7.0 6.5-2 0 12 24 Weeks 18 16 14 12 10 8 6 4 2 0 18 16 14 12 10 8 6 4 2 0 Overall 21% risk reduction p <0.02 42% risk reduction p <0.01 Nocturnal Hypoglycaemia Riddle et al Diabetes Care 2003;26:3080-6. 47% risk reduction p < 0.001 55% risk reduction p < 0.001 Overall Nocturnal Hypoglycaemia Hermansen et al. Diabetes Care 2006;29: 1269

Basal insulin Which type? How to start? How to adjust?

TREAT-TO-TARGET TRIALS Insulin continually titrated to target: Fasting PG 100 mg/dl The starting dose of both insulins was 10 IU Insulin glargine once-daily (evening) n = 367 NPH once-daily (evening) n = 389 Riddle et al 2003 Insulin detemir twice-daily n = 237 NPH twice-daily n = Starting 238 doses were 10 units/iu. If initial premeal PG <126 mg/dl or BMI was <26.0 kg/m2, starting doses were reduced to 6 units/iu. Insulin continually titrated to target: Fasting and pre-dinner PG 108 mg/dl Hermansen et al 2006

Basal insulin Which type? How to start? How to adjust?

1.2.3 STUDY: BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN 785 Insulin naive type 2 diabetes (A1C 8.0%) Receiving 2 or 3 OHAs for 3 months A1C 7.0% RANDOMIZATION RUN-IN PHASE Add Insulin glargine OD 14 weeks Basal insulin + Prandial insulin 1 shot Basal insulin + Prandial insulin 2 shot Basal insulin + Prandial insulin 3 shot Davidson M et al. Endocr Pract 2011;17:395.

ADD BASAL INSULIN Start BASAL INSULIN 10 unit 10.5 9.5 10.2 At 14-wk run-in 288/785 (37%) A1C < 7% HbA1c (%) 8.5 7.5 7.9 6.5 Baseline 14-wk run-in

Maximum dose of Basal insulin Increase insulin dose is associated with weight gain Insulin dose <0.5 u/kg/d decrease HbA1c 0.5% for each increment in insulin dose equal to 0.1 u/kg/d Insulin dose >0.5 u/kg/d decrease HbA1c 0.5% for each increment in insulin dose equal to 0.2 u/kg/d Monnier L. Daibetes Metan 2006;32:7

TIP: BEDTIME INSULIN DAYTIME SULFONYLUREA Start NPH or non peak insulin 10 unit or 0.1-0.2 unit/kg at bedtime Continue Oral hypoglycemic agent Titrate If FPG > 110 mg/dl x 2D 2 unit Keep FPG 90-110 mg/dl Basal dose ~0.5-0.6 unit/kg/d (~50% of Total daily dose)

Efficacy of different OHAs Class of medicine Expected decrease in HbA 1C Biguanide 1.0-2.0% Sulfonylureas 1.0-2.0% Glinides* 0.5-1.5% TZDs 0.5-1.4% -glucosidase inhibitors 0.5-0.8% GLP-1 agonists 0.5-1.0% DPP4 inhibitors 0.5-0.8%

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day (used to on 2500 mg a day, but had diarrhea) Pioglitazone 30 mg a day Her last HbA1C 9%, FPG 220 mg/dl QUESTION 3 ถ าท านเล อกจะให อ นส ล นในผ ป วย รายน ท านจะเร มให อย างไร? A. Continue OHA + NPH 6 u B. Continue OHA + NPH 10 u C. Off SU, Cont MET + NPH 10 u D. Continue OHA + Glargine 10 u E. Off OHA + Mix insulin 15 u bid

Mrs B Currently on Glipizide 20 mg a day Metformin 2000 mg a day NPH 26 unit per day Her last HbA1C 7.8%, FPG 100 mg/dl

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day NPH 26 unit per day Her last HbA1C 7.8%, FPG 100 mg/dl QUESTION 4 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Lifestyle modification B. Check insulin technique C. Add TZD D. Add DPP-IV inhibitor E. Switch to Glargine 20 u

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day NPH 26 unit per day Her last HbA1C 7.8%, FPG 100 mg/dl QUESTION 5 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Add TZD B. Add DPP-IV inhibitor C. Switch to Glargine 20 u D. Add RI 4 u at big meal E. Switch to Mix insulin 14 u bid

WHEN TO INTRODUCE MORE COMPLEX INSULIN REGIMENS? FPG is acceptable, but HbA1c is still high or post prandial higher than goal When aggressive titration is limited by hypoglycemia In insulin deficiency end of type 2 diabetes spectrum maximum dose of basal insulin

Oral Hypoglycemic agents failure Add basal insulin Switch to Premixed Insulin Add Prandial Insulin

572 T2DM 2-3 OADs A1C >7.5% @ screening A1C >7% @ randomization ALL TO TARGET STUDY DESIGN Current OADs 1 m BASAL INSULIN + 2 OADs 3m TTT FPG and pre prandial BG < 100 mg/dl A1C <6.5% BASALINSULIN + 2 OADs 60-week study Premix x 2 + met and/or TZD A1C > 7 BASAL + 1 PRANDIAL+ met and/or TZD B+P x1 + met/tzd 3 m B+P x2 + met/tzd A1C > 7 3 m A1C > 7 B+P x3 + met/tzd 3 m N=192 N=189 N=191 Riddle MC and Rosenstock J et al. ADA 2011, San Diego.

ALL TO TARGET EFFICACY A1C (%) % Patients with A1C <7% 9.5 60 * 49 * 45 8.5 40 39 * 24 * 24 7.5 * * 20 14 6.5 Premixed Basal + 1 shot * P < 0.05 vs. Premixed Basal + 0-3 shot 0 Baseline 60 weeks Premixed Basal + 1 shot Basal + 0-3 shot <7% without hypo

ALL TO TARGET SYMPTOMATIC HYPOGLYCEMIA 15 Event-rates per person-yr 10 5 0 * * Premixed Basal + 1 shot * * Basal + 0-3 shot Basal + prandial Insulin had better efficacy and less hypoglycemia compare to Premixed * P < 0.05 vs. Premixed BG < 70 mg/dl BG < 50 mg/dl

PRANDIAL INSULIN Rapid (Lispro, Aspart, Glulisine) Rapid-acting analogue insulin Onset: <1/2 hr Peak: 1 hr Duration: 3-4 hr Insulin Level Short (Regular) Regular insulin Onset: 1/2 hr Peak: 1-3 hr Duration: 6-8 hr 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours

1.2.3 STUDY: BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN 785 Insulin naive type 2 diabetes (A1C 8.0%) Receiving 2 or 3 OHAs for 3 months A1C 7.0% RANDOMIZATION RUN-IN PHASE Add Insulin glargine OD 14 weeks Basal insulin + Prandial insulin 1 shot Basal insulin + Prandial insulin 2 shot Basal insulin + Prandial insulin 3 shot Davidson M et al. Endocr Pract 2011;17:395.

1.2.3 STUDY: BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN Definition of Main meal Start: 1/10 of total daily dose of BASAL INSULIN Titration Preprandial SMBG during the preceeding 7 calendar days Weekly titration

A1C c (%) 1.2.3 STUDY: BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN Evolution of A1C in the randomized 10.0 9.0 BASAL (alone) 10.19 10.19 10.16 BASAL plus PRANDIAL (patients with A1C >7%) PRANDIAL 1x PRANDIAL 2x PRANDIAL 3x 8.0 7.44 7.40 7.0 7.29 Run in Randomization Wk 8 Wk 16 Wk 24 A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomization

Mean body weight change from baseline (kg) Confirmed symptomatic hypo (event/patient-year) Severe or serious hypo (event/patient-year) 1.2.3 STUDY: BASAL INSULIN PLUS 1, 2 OR 3 DOSES OF PRANDIAL INSULIN 5 4 3 2 3.7 3.8 3.9 20 15 10 12.2 12.9 17.1 0.35 0.30 0.25 0.20 0.15 p=0.043 0.30 0.26 1 5 0.10 0.05 0.10 0 x1 x2 x3 PRANDIAL 0 x1 x2 x3 PRANDIAL 0.00 x1 x2 x3 PRANDIAL p=ns for all other pairwise comparisons Basal + 1, 2 or 3 prandial Insulin had similar efficacy stepwise approach

Oral Hypoglycemic agents failure Add basal insulin Add Prandial insulin at main meal OR breakfast

TIPS: ADDING SINGLE PRANDIAL INSULIN INJECTION Add with the main meal Starting dose 10% of total daily dose, not less than 4 unit/meal Monitor pre-prandial glucose of next meal Target SMBG pre-prandial < 70-110 mg/dl, bedtime 70-120 mg/dl Titration dose, <10 u dose, 10-20 u dose, >20 u add 1 unit add 2 unit add 3 unit

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Glipizide 20 mg a day Metformin 2000 mg a day NPH 26 unit per day Her last HbA1C 7.8%, FPG 100 mg/dl QUESTION 5 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Add TZD B. Add DPP-IV inhibitor C. Switch to Glargine 20 u D. Add RI 4 u at big meal E. Switch to Mix insulin 14 u bid

Mrs B Currently on Metformin 2000 mg a day NPH 30 unit per day RI 10 unit at lunch time Her last HbA1C 8.1%, FPG 130 mg/dl

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Metformin 2000 mg a day NPH 30 unit per day RI 10 unit at lunch time Her last HbA1C 8.1%, FPG 130 mg/dl QUESTION 6 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Add RI 4 u at dinner B. Switch to Mix insulin 15 u bid C. Switch to Mix insulin 20 u at breakfast and 10 u at dinner

Premixed Insulin Human insulin 70/30 Insulin analog 75/25 Insulin analog 70/30

Insulin Effect Mixtures of Pre-meal Insulin Regular/NPH Combined effect B L S HS B

Starting dose? Usually conventional initial approach to dosing premixed insulins in general practice is to prescribe a ratio of 2/3 of the total daily insulin dose in the morning before breakfast and 1/3 in the evening before dinner.

PREMIXED INSULIN DOSING IN ACTUAL PRACTICE: 2/3 IN AM, 1/3 IN PM, OR 50-50? retrospective, observational, descriptive study was designed to examine the use of premixed insulins in a community-based endocrinology practice to analyze the ratio, for morning and evening doses of premixed insulin. the premixed insulin dosing ratio of evening dose to TDD significantly differs from the standard value of 0.33 and is on average close to 0.5 or 50%

How about the SU, should we stop? The only consistent advantage of continue SU is: Reduced insulin dose requirements, which may result in less daily injections Easier dose titration Improved compliance These potential benefits must be balanced against the side effects

Dose Titration Blood Glucose Adjust Insulin* Prebreakfast <70 mg/dl Decrease PM 1-2 U 140-250 mg/dl Increase PM 1-2 U >250 mg/dl Increase PM 2-4 U Presupper <70 mg/dl Decrease AM 1-2 U 140-250 mg/dl Increase AM 1-2 U > 250 mg/dl Increase AM 2-4 U Person J. Diabet Educat 2006;32:195

60 years old Thai female Type 2 DM Diagnosed 10 years ago Co-morbid diseases: HT, Dyslipidemia BW 60 kg Currently on Metformin 2000 mg a day NPH 30 unit per day RI 10 unit at lunch time Her last HbA1C 8.1%, FPG 130 mg/dl QUESTION 6 ท านจะให การร กษาผ ป วยรายน อย างไร? A. Add RI 4 u at dinner B. Switch to Mix insulin 15 u bid C. Switch to Mix insulin 20 u at breakfast and 10 u at dinner

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