Starting Insulin by M Daoud

Diabetes Mellitus Insulin Therapy

Dr. Mohammad DaoudConsultant Endocrinologist

KAMC/ NGHA - Jeddah –Saudi Arabia

Objectives

Introduction

Insulin :Choices and Profiles

Guidelines

Adding / Switching to Insulin

CASE:150 - Year-old female ; 8 years history of DM type 2 Meds: Metformin 1gm BD and Gliclazide MR 120 mg , Pioglitazone 30 mg ,and Sitagliptin 100 mg

Her diet and physical activity is excellent

Her glucose reading at home ; unsatisfactory

Last HbA1c 8.5- 9%

Best next step in management ?

CASE:261 - Year-old obese male patient

DM Type 2 for about 15 years

On maximum doses of MFN and SU

His FBS 180- 220 mg/dl (10-12 mmol/l)Random readings 200-280 mg/dl (11-15.5 mmol/l)

HbA1c of 10.5 % - 11% despite being compliant to treatment and diet

You are asked to help him getting better control?

Insulin glargine

2000

Treatment Milestones in Diabetes

Biguanides

1960

Insulintherapy

1922

Sulphonylureatherapy

1950s

Insulin pump

Late1970s

NPH=neutral protamine Hagedorn; DCCT=Diabetes Control and Complications Trial; UKPDS=United Kingdom Prospective Diabetes Study.Data from Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpa696.htm. Accessed 18 March 2003.Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm. Accessed 18 March 2003.

NPHinsulin

1946

Lente insulin therapy

1952

HbA1ctesting

1975

DCCT

1993

Rapid-acting insulin

analogues

1996

UKPDS

1998

Blood glucose self-monitoring

Glycemic ControlRecommendations

EMPOWER the Patient

Should be able to Use data

Adjust Therapy.

(E)

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S21–S22

ADA-2015

Correlation of A1C with estimated Average Glucose

A1C (%) Mean plasma glucose mg/dl

6 ̴ 120

7 ̴ 150

8 ̴ 180

9 ̴ 210

10 ̴ 240

11 ̴ 270

12 ̴ 300

ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S23; Table 8

Insulin Education and Initiation

Basal Insulin: Pharmacokinetics

Suppress hepatic glucose production Maintain near normo-glycemia in the fasting

state

Nutritional Insulin:Meal related=Prandial

Control postprandial hyperglycemia

RAARAA RAA

RAA=

RAA RAA RAA

RAA=

Mixed Insulin Humilin 70/30 or Mixtard

70% NPH , 30 % RI

Lispro-Mix 25/75 , 50/50Lispro /Lispro protamine

Novo-Mix -30/70: Aspart /Aspart protamine

Mix from two separate vialsEx: RI and NPH

Mixed Insulin - ADA GuidelinesNot recommended for Type 1 DM patients

Type 2 DM patient: If well controlled …continue

Don’t mix Glargine / Detemir with other insulin : Different PH

NPH + RI mixing …Use immediately

RAI (ex: Lispro / Aspart / Glulisine) + NPH …. use within 15 minutes

Our Goal

To Mimic Normal Physiology

CASE: 150 - Year-old female ; 8 years history of DM type 2 Meds: Metformin 1gm BD and Gliclazide MR 120 mg , Pioglitazone 30 mg ,and Sitagliptin 100 mg

Excellent diet and physical activity

Body weight 70 kg, BMI 28

His SMBG at home ; Unsatisfactory

How will you asses her glycemic control ?

HbA1c

Glucose monitoring (SMBG)

How will you asses his glycemic control ?

HbA1cLatest HbA1c 8.5 %- 9 %

What kind of monitoring will you do ?

Fasting , Pre-meals and @ Bed time

Vs

Fasting , Post-meals and @ Bed time

HbA1c = Fasting Blood Glucose and Postprandial Glucose

Case #1

With higher HbA1C : Pre-meal glucose readings

contribute more to the HbA1C

With HbA1C closer to target ( ex: <8-8.5%)

Post-meal glucose readings contributes more to the HbA1C value

Breakfast Lunch Dinner Bedtime

Before After Before After Before After

Day1 11.7 9.0 7.2 7.8

Day2 10.4 8.5 6.9

Day3 9.5 9.6 7.8

Day4 9.7 8.9 6.5

Day5 10.8 8.5 9.5

SMBG Record

Case #1 Summary

She is on maximum doses of oral agents…

still she has : Suboptimal glycemic control ; A1c

>7% High BG levels, particularly in the

morning (fasting)

ADA-2015

Insulin Regimens

Basal

Basal +

MDI

Pre-mixed

What insulin regimen would you

prescribe?



Day1 11.7 9.0 7.2 7.8

Day2 10.4 8.5 6.9

Day3 9.5 9.6 7.8

Day4 9.7 8.9 6.5

Day5 10.8 8.5 9.5

SMBG Record

Fasting / Pre-Prandial 80-130 mg /dl ~ 4.5 - 7.5 mmol/L

Post--Prandial 140-180 mg /dl ~ 8 - 10 mmol/L

Case #1

Basal insulin Easy choice : single injection

(at bedtime)

“Breaks the Ice”

ADA 2015

Case #1

Glargine or Detemir 15-20 units added at Bedtime (weight 70 kg)

Or Start a dose of 10 units

Titrate every 2-3 days

Pre-meal /FPG is at target : 80-130 mg/dl (about

4.5 - 7.5 mmol/L )

Case #1

3 months later : Now at 28 units of Glargine or Detemir at Bedtime....

HbA1c 6.8%Breakfast Lunch Dinner Bedtime


Day1 5.7 8.0 8.2 6.8

Day2 6.4 9.0 6.8

Day3 7.0 7.6 6.8

Day4 5.9 7.8 7.5

Day5 6.0 9.0 8.5

Case #1Oral agents on board now ?

Metformin Keep unless CI ISS /SU keep on board or decrease

DPP4 - Keep / less amount of insulin neededGlitazones : Decrease

Watch for fluid retention/stop if needed

Case #1

4 years later : Now at 40 units of Glargine or Detemir at Bedtime....

HbA1c 8.2%Breakfast Lunch Dinner Bedtime


Day1 7.5 9.0 12.5 8.2 9.8

Day2 6.9 11.9 9.0 10.5 11.8

Day3 6.8 7.6 10.2

Day4 5.9 13.0 7.8 9.9 9.5

Day5 7.5 9.0 12 8.5

Are you surprised ?

ADA=American Diabetes Association; HbA1c=hemoglobin A1cAdapted from UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998; 352: 854–865.

UKPDS: Glycemic Control Worsens Over Time

Med

ian

HbA

1c (%

)

0 2 40

6

7

8

9

6 8 10Time from Randomization (y)

Upper limit of normal range (6.2%)

ADA goal (7.0%)

Conventional (n=200) Insulin (n=199)

Chlorpropamide (n=129)Glibenclamide (n=148)

Metformin (n=181)

Diabetes Mellitus Type 2 is a Progressive Disease

SA- GLA-11-11-04

43

When basal insulin is not enough

• Step 1: Think first of titrating the basal insulin dose till reaching FBG target (Often under-dosage)

• Step 2: Shift to Basal Plus or Basal-bolus (MDI) regimen :• Number of daily injections up to 4 (1+3)• Inconvenience • Risk of hypoglycemia & Weight gain

Add prandial insulin dose (s) as per guidelines

Case #1

4 years later : Now at 40 units of Glargine or Detemir at Bedtime.... HbA1c 8.2%



Day1 7.5 9.0 12.5 8.2 9.8

Day2 6.9 11.9 9.0 10.5 11.8

Day3 6.8 7.6 10.2

Day4 5.9 13.0 7.8 9.9 9.5

Day5 7.5 9.0 12 8.5


Case #1 Main issue now is postprandial

hyperglycemia

Add on : to main meal or all meals RI / RAI

Ex : Aspart /Glulisine/ Lispro Insulin 4 u/ meal

Adjust according to SMBG

Basal +

ADA 2015

Case #1

Titrate every 2-3 days

Post-meal target 140-180 mg /dl (about 8- 10 mmol/L )

Case # 13-4 months later : Now at 40 units of

Glargine or Detemir and Aspart 14- 12 -12- at Bedtime.... HbA1c 6.5%



Day1 7.5 9.0 9.5 8.0 7.8

Day2 6.9 8.9 7.0 9.5 8.8

Day3 6.8 7.6 8.0

Day4 5.9 8.0 7.8 7.9 9.5

Day5 7.5 9.0 7.8 8.2

Well done

Case #1

Now on Basal 40 unitsMeal related 38 unitsAlmost... 50% / 50%

Case #1

You may chose to use Basal +i.e

Basal insulin + meal related insulin added to main meal or

the meal with highest post-prandial glucose

If not adequate …other meals can be covered also

Case #1

You may chose to use Premixed Insulin BID

Or Premixed analogues :

Ex: NovoMix-30/70 or Humalog-Mix 25 in 2-3 doses

Mixed Insulins

ADA 2015

CASE: 268-year-old obese male patientDM Type 2 for about 15 years

On SU and MFN maximum doses

His FPS 180- 220 mg/dl (> 10-12 mmol/l)Random readings 200-280 mg/dl (> 11-15.5 mmol/l)

HbA1c of 10.5% despite compliance to Rx and TLC

You are asked to help him getting better control?

CASE: 2

He has impaired visionPolyuria , Polydypsia

(Weight 70 kg, Height 170 cm)

Serum Creatinine 1.15 mg/dl (105 nmol/L) e-GFR ~ 50 ml/min

CASE: 2

Before BF 2hr PBF Pre Dinner 2hr PP

Day 1 195 230 280 245

Day 2 180 200 205 230

Day 3 220 250 220 210

Case #2 Summary

Case review Uncontrolled / Symptomatic

hyperglycemia High BG levels all over the screen ;

fasting and post-meals

He is on maximum doses of oral agents

Co-morbidities : Renal impairment +…

ADA/EASD and AACE position statement 2012: individualized HbA1c targets

Inzucchi et al. Diabetologia 2012;55:1577–96

6.0 – 6.5% < 8.0%< 7.0%HbA1c target

CASE: 2


Day 1 195 230 280 245

Day 2 180 200 205 230

Day 3 220 250 220 210

What is the proper glycemic targets for this patient ? Is it …

Fasting / Pre-Prandial 80-130 mg /dl ~ 4.5 - 7.5 mmol/L


CASE: 2

Before BF 2hr PBF Post Dinner 2hr PP

Day 1 195 230 280 245

Day 2 180 200 205 230

Day 3 220 250 220 210

Safer targets can be justified for this patient Like…

Fasting / Pre-Prandial 100-150 mg /dl

Post--Prandial 150-200 mg /dl

• Age: Older adults-Reduced life expectancy-Higher CVD burden-Reduced GFR-At risk for adverse events from polypharmacy-More likely to be compromised from hypoglycemia

Less ambitious targetsHbA1c <7.5–8.0% if tighter

targets not easily achievedFocus on drug safety

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

CASE: 2

Before BF 2hr PBF Pre Dinner 2hr PPDay 1 195 230 280 245 Day 2 180 200 205 230Day 3 220 250 220 210 Start TDD of 0.3- 0.5 unit /kg

Wt. 70 kg 0.4 unit /kg

(you can start with lower limit and adjust)

About 28 units total

CASE: 2

TDD of 0.3- 0.5 up to 0.8 unit /kgWt 70 kg 0.4 unit /kg

Start at 28 units total

Then SMBG …and adjust

Basal/ Bolus Glargine 16 u HSRAI 4-4-4 u TID

Premixed Mixtard 18/10

Aspart Mix (30/70)18/10 OR 12-8-8

CASE: 2

Started Premixed Mixtard 18/10


Day 1 195 230 280 245 Day 2 180 200 205 230Day 3 220 250 220 210

CASE: 2

Premixed Mixtard 18/10

Dose adjusted gradually to 24 /14


Day 1 145 150 188 125 Day 2 150 148 185 145Day 3 152 140 190 150

CASE: 2

4 weeks later On Premixed Mixtard 32 /16


Day 1 122 89 138 75 Day 2 110 80 145 85Day 3 116 100 120 70

CASE: 2

2 months later Premixed

Mixtard 32 /16

HbA1c 10.5 % to 8.6%Frequent hypoglycemia ?!!


Day 1 122 89 138 75 Day 2 110 60 195 55Day 3 260 100 120 70

CASE: 2


Day 1 195 230 280 245 Day 2 180 200 205 230Day 3 220 250 220 210 Basal/ Bolus

0.5 u/kg

18 units Detemir / Glargine

Aspart 6 units tid

CASE: 2


Day 1 144 200 120 195 Day 2 160 190 95 200Day 3 175 200 110 210

1 week later Increased Glargine …18 to 22 uIncreased Aspart …10 / 6 / 10

CASE: 2


Day 1 135 170 100 180 Day 2 150 160 110 190Day 3 140 136 95 170

4 week later Increased Glargine …22 to 26 units

Increased Aspart …10 / 6 / 12

CASE: 2


Day 1 135 150 100 150 Day 2 120 140 110 140Day 3 110 136 95 160

3-4 Months later Glargine …30unitsAspart …12 / 8 / 14

HbA1c 10.5% to 7.6%

CASE: 2

Glargine …30unitsAspart …14 / 8 / 12

Basal 30 unitsPrandial 34 units Almost 50/50

0.5 to 0.9 u /kg

CASE: 2Oral agents on board now ?

Metformin Keep unless CI ISS /SU Stop

DPP4 - Keep / less amount of insulin needed

Glitazones : Decrease Watch for fluid retention/stop if needed

To Conclude…

Summary (continue)

Basal Insulin alone …Break the Ice 0.1-0.3 u /kg or fixed 10 u and adjust

Early on , Don’t switch ….Add(esp. insulin secretagogues; SU /Glinides)

Metformin: Keep unless CI ( Lower insulin doses and less weight gain)

TZDs …decrease or stop (Less risk of fluid retention /heart failure)

Summary (continue)

Basal –Bolus Insulin

TDD = 0.3-0.5 u /kg Basal Insulin 40-50 % Meal related :50-60 %

Insulin secretagogues (SU /Glinides): No need

Keep Metformin / maybe TZDs

Summary (continue)

Premixed / Bi-Phasic

TDD = 0.3-0.5 u /kg 2/3 am and 1/3 pm OR

2-3 doses (premixed analogues) 10% adjustment role

Drawbacks:Hypo /Weight gain/ Larger doses

Insulin secretagogues (SU /Glinides): No needKeep Metformin / maybe TZDs

Summary

Start Low …and Go Slow …monitor and adjust Based on a “Trend”

Avoid hypoglycemia

Patient teaching …Core part of the team

B

https://www.aace.comEducation

Certification..

Diabetes Resource Center..

Inpatients Vs Outpatients

Health & Medicine

Starting Insulin by M Daoud