The Art and Science of The Art and Science of InsulinInsulin

Thomas Repas D.O.Thomas Repas D.O.Diabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, WisconsinDiabetes, Endocrinology and Nutrition Center, Affinity Medical Group, Neenah, Wisconsin

Member, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Inpatient Diabetes Management Committee, St. Elizabeth’s Hospital, Appleton, WIMember, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program Member, Diabetes Advisory Group, Wisconsin Diabetes Prevention and Control Program

Website: www.endocrinology-online.comWebsite: www.endocrinology-online.com

Overview

• Goals and Purpose of Insulin Therapy

• Barriers to the use of Insulin

• Current Concepts in Insulin Therapy

• Basal/Bolus Insulin

• Sliding Scales

• Insulin Pump Therapy

• Future of Insulin

• Conclusion

!

Purpose of Insulin Therapy

• Prevent and treat fasting and postprandial hyperglycemia• Permit appropriate utilization of glucose and other nutrients by

peripheral tissues• Suppress hepatic glucose production• Prevent acute complications of uncontrolled diabetes• Prevent long term complications of chronic diabetes

The Goal of Insulin Therapy:The Goal of Insulin Therapy:Attempt to Mimic Normal Pancreatic FunctionAttempt to Mimic Normal Pancreatic Function

Schade, Skyler, Santiago, Rizza, “Intensive Insulin Therapy,” 1993, p. 131.

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PLA SM AG LUC O SE

m g /d l

B L S HS

PLA SM A FREEIN SULIN

u/m l

WHAT!?Did you say

INSULIN?!INSULIN?!

Barriers to Barriers to the Use of the Use of

Insulin Insulin

Patient Concerns About Insulin

• Fear of injections

• Perceived significance of need for insulin

• Worries that insulin could worsen diabetes

• Concerns about hypoglycemia

• Complexity of regimens

Help Patient Accept and Prepare for Insulin Therapy

• Address patient concerns– Dispel fear by countering misconceptions– Review rationale for insulin use– Explain that insulin

– Can be incorporated into lifestyle

– Causes only modest weight gain

– Is a common course of treatment for this progressive disease

• Promise patient support and close follow-up– Monitoring can prevent hypoglycemia

– Today’s technology can facilitate daily injections and readings

Barriers to Insulin Therapy : Common Medical Concerns

Insulin therapy in type 2 diabetes might cause:

• Worsening Insulin Resistance?

• More Cardiovascular Risk?

• Weight Gain ?

• Hypoglycemia?

6-8

Insulin Sensitivity in Glucose Clamp Studies: Improved by Insulin Treatment

Scarlett, et al. Diabetes Care. 1982;5:353-363; Andrews, et al. Diabetes. 1984;33:634-642; Garvey, et al. Diabetes. 1985;34:222-234.

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GarveyAndrewsScarlett

BaselineAfter Insulin

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trol

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ues

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Cardiovascular RiskMortality After MI Reduced by Insulin Therapy in the DIGAMI Study

Malmberg, et al. BMJ. 1997;314:1512-1515.

All Subjects(N = 620)Risk reduction (28%)

P = .011

Standard treatment

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Low-risk and Not Previously on Insulin(N = 272)Risk reduction (51%)

P = .0004

IV Insulin 48 hours, then 4 injections daily

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Reassurance About Common Concerns

Insulin Therapy in Type 2 DM

• Improves Insulin Sensitivity by Reducing Glucotoxicity

• Reduces Cardiovascular Risk

• Causes Modest Weight Gain

• Rarely Causes Severe Hypoglycemia

• Patients fears and concerns can be addressed by education

6-15

Current Concepts in Current Concepts in Insulin TherapyInsulin Therapy

Comparison of Human Insulins and Analogues

Insulin Onset of Duration ofPreparations Action Peak Action

Lispro/Aspart 5-15 minutes 1-2 hours 3-5 hours

Human Regular 30-60 minutes 2-4 hours 4-8 hours

Human NPH/Lente 1-4 hours 4-12 hours 10-20 hours

HumanUltralente 6-8 hours Unpredictable 16-20 hours

Glargine 2-3 hours Flat ~24 hours

The time course of action of any insulin may vary in different individuals, or at different times in the same individual. Because of this variation, time periods indicated here should be considered general guidelines only.

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Twice-daily Split-mixed Regimens

Regular

NPH

B SL HS

Insu

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ect

B

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Multiple Daily Injections (MDI)NPH + Regular

Regular NPH

NPH at AM and HS + Regular AC NPH at HS + Regular AC

Insu

lin

Eff

ect

B SL HS B

Insu

lin

Eff

ect

B SL HS B

Regular NPH

6-24

Multiple Daily Injections (MDI)Ultralente + Regular

Regular

Ultralente

B SL HS

Insu

lin

Eff

ect

B

6-25

Limitations of Human Regular Insulin

• Slow onset of action– Requires inconvenient administration: 20 to 40 minutes prior

to meal – Risk of hypoglycemia if meal is further delayed– Mismatch with postprandial hyperglycemic peak

• Long duration of activity– Up to 12 hours’ duration– Increased at higher dosages– Potential for late postprandial hypoglycemia

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Basal and Bolus InsulinsBasal and Bolus Insulins

6-16

The Basal/Bolus Insulin Concept

• Basal Insulin– Suppresses glucose production between meals and overnight– Nearly constant levels – 50% of daily needs

• Bolus Insulin (Mealtime or Prandial)– Limits hyperglycemia after meals– Immediate rise and sharp peak at 1 hour – 10% to 20% of total daily insulin requirement at each meal

6-20

Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific

profile

Insulin and Glucose Patterns: Normal and Type 2 Diabetes

Polonsky, et al. N Engl J Med. 1988;318:1231-1239.

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Glucose Insulin

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Time of Day

0600 1000 18001400 02002200 0600

Time of Day

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B L SB L S

Normal

Type 2 Diabetes

mg/

dL

U/m

L

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Rapid-acting Analogues: Clinical Features

• Insulin profile more closely mimics normal physiology

• Convenient administration immediately prior to meals

• Faster onset of action

• Limit postprandial hyperglycemic peaks

• Shorter duration of activity

– Reduced late postprandial hypoglycemia

– But more frequent late postprandial hyperglycemia

• Need for basal insulin replacement revealed

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Rapid-acting Insulin Analogues: Lispro and Aspart

400

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MealSC injection

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Time (min)90 120 180 210150 240

Lispro

Regular Human

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MealSC injection

Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506.

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Multiple Daily Injections (MDI)NPH + Mealtime Lispro

NPH at AM and HS + Lispro AC NPH at HS + Lispro AC

Insu

lin

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Insu

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B SL HS B

LisproNPH

LisproNPH

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Limitations of Human NPH, Lente, and Ultralente

• Do not mimic basal insulin profile– Variable absorption

– Pronounced peaks

– Less than 24-hour duration of action

• Cause unpredictable hypoglycemia– Major factor limiting insulin adjustments

– More weight gain

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The Quest for Basal Insulin Replacement

Lispro

NPH

Mealtime Lispro + NPH and NPH at HS

B SL HS

Insu

lin

Eff

ect

B

Bolli, et al. Diabetologia. 1999; 42:1151-1167.

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The Ideal Basal Insulin . . .

• Mimics normal pancreatic basal insulin secretion

• Long-lasting effect around 24 hours

• Smooth, peakless profile

• Reproducible and predictable effects

• Reduced risk of nocturnal hypoglycemia

• Once-daily administration for convenience

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Profiles of Various Basal Insulins

Glargine

NPH

Ultralente

CSII

n = 20 T1DMn = 20 T1DMMean Mean ± SEM± SEM

SC insulin

4.04.0

3.03.0

2.02.0

1.01.0

00

2424

2020

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Time (h)

mg

/kg

/min

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l/kg

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µ

SC=subcutaneous; CSII=continuous subcutaneous insulin infusionSC=subcutaneous; CSII=continuous subcutaneous insulin infusionLepore M et al. Lepore M et al. Diabetes.Diabetes. 2000;49:2142-2148. 2000;49:2142-2148.

Long-Acting Insulins: Ultralente and Glargine

Ultralente• Injected once or twice daily• Onset within 6–8 hours• Peak effect within 10–20 hours

Glargine• 24-hour, long-acting recombinant human insulin analogue

has no peak• Cannot be diluted or mixed with other insulins or solutions• Administered once daily

– In combination therapy, glargine given at bedtime; rapid- or short-acting given during the day

Glargine vs NPH Insulin in Type 1 DiabetesAction Profiles by Glucose Clamp

Lepore, et al. Diabetes. 1999;48(suppl 1):A97.

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Bedtime Glargine vs NPH, With Mealtime Regular

*P < .01 (change from baseline to endpoint within each group)**P < .02 (compared to NPH)

Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.

Baseline8.5 ± 1

* **

*

8.8 ± 1 11.1 ± 4 10.6 ± 4Baseline

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NocturnalHypoglycemia

FPG(mmol/L)

HbA1c(%)

NPH Glargine

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Patien

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Bedtime Glargine vs NPH, With Mealtime Regular

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HypoglycemiaWeight Gain

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NPH Glargine

Patien

ts (%)

*P < .0007**P < .02 (compared to NPH)

Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100.

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Insulin GlargineSummary of Completed Trials

• Glucose-insulin clamp studies of Glargine vs NPH

– Smooth, continuous release from injection site

– Longer duration of action with effect for about 24 hours

– Peakless profile

• Equivalent absorption rates at various injection sites

• Clinical efficacy equivalent to NPH, with significantly less nocturnal

hypoglycemia

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AllAllType 1 diabetics should be on aType 1 diabetics should be on a

basal / bolus insulin regimenbasal / bolus insulin regimento control glucose while minimizing to control glucose while minimizing

hypoglycemiahypoglycemia

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However over time,However over time,most type 2 diabetics will also needmost type 2 diabetics will also need

both basal and mealtime insulinboth basal and mealtime insulinto control glucoseto control glucose

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Beginning Insulin TherapyBeginning Insulin Therapy

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When Oral Medications Are Not Enough

• Watch for the following signs– Increasing BG levels

– Elevated A1C

– Unexplained weight loss

– Traces of ketonuria

– Poor energy level

– Sleep disturbances

– Polydipsia

• Next steps– Make a decision to start insulin

– Offer patient encouragement, not blame

Remind the patient of disease progression…

Typical Diagnosis of Diabetes

Severity of Glucose Intolerance

Years to Decades

Normal Blood Normal Blood GlucoseGlucose

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Risk of Macrovascular ComplicationsRisk of Macrovascular Complications

Insulin Insulin ResistanceResistance

IGTIGT

Insulin SecretionInsulin Secretion

Postprandial GlucosePostprandial Glucose

Risk of Microvascular ComplicationsRisk of Microvascular Complications

Fasting Blood GlucoseFasting Blood Glucose

Frank Frank DiabetesDiabetes

NGTNGT

Worsens with Time

Initiating Insulin Therapy in Type 2 Diabetes

• Let blood glucose levels guide choice of insulins– Select type(s) of insulin and timing of injection(s) based on pattern of

patient’s sugar (fasting, lunch, dinner, bedtime)

• Choose from currently available insulin preparations– Rapid-acting (mealtime): lispro, aspart

– Short-acting (mealtime): regular insulin

– Intermediate-acting (background): NPH, lente

– Long-acting (background): ultralente, glargine

– Insulin mixtures

• Provide long-acting or intermediate-acting as basal

and rapid-acting as bolus• Titrate every week

Goal: to approximate endogenous insulin secretion…

Starting With Basal Insulin: Advantages

• 1 injection with no mixing• Slow, safe, and simple titration• Low dosage• Limited weight gain• Effective improvement in glycemic control

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B SL HS B

Insu

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Eff

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Metformin

Glargine

TZD

B SL HS B

lispro

Glargine

Insu

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Eff

ect

Glargine at HS + Oral Agents or Mealtime Lispro

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Starting with Basal Insulin

• Continue oral agent(s) at same dosage (eventually stop secretegogue)• Add single, evening insulin dose (around 10 U)

– Glargine (bedtime or anytime?)– NPH (bedtime)– 70/30 (evening meal) or 75/25

• Adjust dose by fasting BG • Increase insulin dose weekly as needed

– Increase 4 U if FBG >140 mg/dL

– Increase 2 U if FBG = 120 to 140 mg/dL • Treat to target (usually <120 mg/dL)

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Advancing Bolus/ Adding Bolus Insulin

• Indicated when FBG acceptable but– HbA1c not at goal and/or– Postprandial BG not at goal (<140mg/dl)

• Insulin options– To Glargine, add mealtime Regular or Lispro – To bedtime NPH, add morning NPH and

mealtime Regular or Lispro– To suppertime 70/30 or 75/25, add morning 70/30 or 75/25

• Oral agent considerations– Usually stop secretagogue (it is redundant to be on insulin and secretagogue)– Continue metformin and TZD for additional glycemic and other benefits

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Changing from Other regimens to Changing from Other regimens to Basal/Bolus InsulinBasal/Bolus Insulin

~50%

Basal*

Total Daily DoseTotal Daily Dose(~70-75% of prior insulin regimen TDD)(~70-75% of prior insulin regimen TDD)

~50%

Bolus*

Usually divided into 3 premeal dosesUsually divided into 3 premeal doses*Range: 40 to 60%*Range: 40 to 60%

An Example:

• Mr. M: 58 yo with history type 2 diabetes for 8 years– In addition to oral meds, he is on 70/30 insulin: 30 u AM and 15 u PM– Current Total Daily Dose = 45 u of 70/30– However, he has been having difficulty with wide glycemic excursions

• After discussing his options in detail, he is willing to begin basal/bolus regimen:

• New TDD= 45 u x .75 = 33.75 = 34 u– Basal = 17 u Lantus at bedtime– Bolus = 17 u total / 3 = 5.6 u = 5 u Humalog with meals

Another method

• Same patient: Mr. M on 70/30 insulin: 30 u AM and 15 u PM– Current Total Daily Dose = 45 u of 70/30

• Instead, some clinicians prefer to instead calculate the new basal/bolus doses independently of each other– Current Basal= 0.70 x 45 u TDD = 31.5 u N– Current Bolus= 0.30 x 45 u TDD = 13.5 u R

• Then, use 70 to 75% of prior NPH, but divide prior short acting into 3 premeal doses– New Basal= 0.75 x 31.5 u N = 24 u Lantus– New Bolus= 13.5 u R / 3 = 4.5 u (round up or down) premeal Humalog

So which method is best?

• This is where the “Art of Medicine” comes in:

– If patient has been having difficulty with hypoglycemia, then start any new insulin regimen with conservative doses

– If patient, on the other hand, has been having hyperglycemia, then one can be more aggressive

Remember: every patient is an individual!

Fine Tuning of Bolus DosesFine Tuning of Bolus Doses

Bolus Dose Insulin

• Premeal boluses: – Taken before meals

– Covers mealtime carbohydrate intake

– Prevents postprandial hyperglycemia

• Correction or supplementation boluses:– Used to Correct and treat hyperglycemia

– May be given alone between meals for hyperglycemia

– May be given to supplement already scheduled insulin to cover premeal hyperglycemia

Calculation of Premeal Bolus Doses

Methods

1. Estimate patient’s individual insulin-to carb ratio

2. Formula: 500 Rule

3. Weight based Method

* Bode et al: Diabetes Care 1994: 19: 324-7

Determination of Insulin to Carb Ratio: Method 1

EXAMPLE: Estimate 1 unit of insulin: 15 gm carb

Note: 1 unit: 15 gm is often a “safe” starting pointfor most patients . . .

Determination of Insulin to Carb Ratio: Method 2

Use the 500 Rule:

Divide 500 by TDD= 1 unit insulin to ___ gm CHO as bolus

EXAMPLE: 500 ÷ 34 u= 15

Bolus ratio is 1 u insulin : 15 gm CHO

Weight (lb) Insulin u: CHO gm *

100-109 1: 16

110-129 1: 15

130-139 1: 14

140-149 1: 13

150-169 1: 12

170-179 1: 11

180-189 1: 10

190-199 1: 9

200+ 1: 8

Determination of Insulin to Carb Ratio: Method 3

*Walsh, Pumping Insulin, 2nd ed.Weight Based Method

Premeal Insulin and Carb Premeal Insulin and Carb CountingCounting

Macronutrient Conversion to Blood Glucose

Carbohydrate Counting

BenefitsAllows for variation in appetite

and preferences

Increases variety of food choices

Can be used to match insulin bolus doses to food intake

Carb Counting and Insulin Bolusing

Sample Meal 1 c. orange juice 30 g2 slices toast 30 g½ c. oatmeal 15 g1 soft-cooked egg1 tsp margarineCoffee & 1 T cream_____________________Total CHO: 75 gInsulin bolus: 5 units

Sample Meal2 slices wheat bread 30 g2 oz. turkey breastLettuce leaf, tomato slice1 tsp mayonnaise6-8 3-ring pretzels 15 g2 small choc cookies 15 gDiet soda, 16 oz__________Total CHO: 60 gInsulin bolus: 4 units

Insulin-to-Carb Ratio

EXAMPLE: 1 unit insulin: 15 grams CHO

Fine Tuning: Meal Bolus Doses

• Adjust bolus based on post-meal BGs

• Carbohydrate counting or pre-determined meal portion

• Individualize insulin to carbohydrate dose or insulin to premeal dose

Correction Boluses for Correction Boluses for HyperglycemiaHyperglycemia

Correction Bolus Insulin

• To be taken to correct for hyperglycemia

• Based on insulin sensitivity factor

• Goal is for correction bolus to lower blood glucose to within 30 to 50 mg/dl of target value

Insulin Sensitivity Factor

1 unit of insulin will blood glucose by: mg/dl

Regular: 1500 Rule Humalog: 1800 Rule

1500 or 1800 divided by TDD= amount of blood glucose lowered by 1 unit insulin

Use to high blood glucose

Insulin Sensitivity FactorEXAMPLE

TDD is 34 units

1500 Rule: 1500 ÷ 34 = 44 1 unit of Regular bg 44 mg/dl 1800 Rule: 1800 ÷ 34 = 53 1 unit of Humalog bg 53 mg/dl

Combining Correction and Premeal Boluses

If a patient’s insulin to carb ratio is 1:15gm and the insulin correction factor is 1: 50 mg/dl and their premeal BG goal is < 110 mg/dl…..

What dose of Humalog would you give premeal if their actual premeal BG = 210 mg/dl and they are about to eat a turkey sandwich (30 gms carbs)?•210 mg/dl –110 mg/dl = 100/50 = 2 u for correction•30 gms carbs/15 = 2 u for mealtime carb coverage

Premeal total insulin bolus dose = 4 u

A Quick Word on using Sliding A Quick Word on using Sliding Scale Insulin….Scale Insulin….

Don’t!Don’t!

Instead of Sliding Scale....

• Basal insulin is necessary even in the fasting state • Sliding scales do not provide physiologic insulin needs• Sliding scales often result in “chasing” of blood sugars• There can be wide glycemic excursions

Remember: Just because a diabetic’s FBG is <150 does not mean that they need no insulin!

Think Supplementation or Correction Scale…

The Solution:

•If one must use an insulin scale in an outpatient or stable inpatient setting:

• In acutely ill hospitalized diabetics: use continuous IV insulin

• Insulin scale should only supplement a routine scheduled regimen of basal and premeal insulin •May use to correct for hyperglycemia between scheduled doses of insulin•It should NEVER be ordered such that the scale is the only source of insulin for the patient

The FutureThe Futureof of

Insulin TherapyInsulin Therapy

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The Future of Insulin

• Inhaled Insulin: Exubra, others

• Oral / Buccal Insulin: Oralin

• New basal insulin: Insulin Detemir

• New Rapid Acting Insulin Analogue

• Other: Closed Loop Systems (Artificial pancreas)

6-54

Oral Agents + Mealtime Inhaled Insulin: Effect on HbA1c

*P < .001

Weiss, et al. Diabetes. 1999;48(suppl 1):A12.

10

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Oral Agents +Inhaled InsulinOral Agents Alone

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Hb

A1c

(%

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Summary: Insulin Therapy

• Replaces complete lack of insulin in type 1 diabetes

• Supplements progressive deficiency in type 2 diabetes

• Basal insulin added to oral agents can be used to start

• Full replacement requires basal-bolus regimen

• Hypoglycemia and weight gain are main medical risks

• New insulin analogues and injection devices facilitate use