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Basal Insulin Therapy

Ted D. Williams

PharmD Candidate

OSU College of Pharmacy

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Initiating Insulin Therapy

• GC– Type 2 Diabetic for 10 years is maxed out on

Metformin and glyburide– AM FBG 275, A1C 10%– PCP orders glargine titration

• CC– Type 2 Diabetic for 10 years is maxed out on

Metformin and glyburide– AM FBG 90, A1C 9.0%– PCP orders glargine titration

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Modifying Insulin Therapy

• CB– Type 2 Diabetic for 3 years– Taking 1000mg Metformin BID, 10mg glyburide BID, NPH

10units QPM– Complains of daytime hypoglycemia– PCP orders D/C NPH and convert to detemir 10units QPM– A1C 7%, FBG 120

• LS– Type 2 Diabetic for 5 years– Taking 1700mg Metformin XR QPM, 5mg glyburide BID, NPH 10

units QPM– Complains of nighttime hypoglycemia– A1C 7%, FBG 60– PCP orders D/C NPH and convert to detemir 10units QPM

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Switching to Insulin Therapy

• NT– Type 2 diabetes for 8 years– Metformin 500mg BID, Glyburide 10mg BID– A1C 8%, FBG 170– PCP orders D/C Glyburide 10mg BID and

begin detemir titration based on PREDICTIVE Trial which shows detemir has better control, less weight gain, and less hypoglycemia than glyburide

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Objectives

• Pathophysiology– Normal Insulin Patterns – Type I vs. Type II Diabetes– Compare normal and diabetic insulin secretion patterns

• Kinetics of insulin analogs• Laboratory values and relevance to pharmacotherapy• Compare intermediate and long acting insulin analogs• Review and summarize recent clinical trials on

intermediate and long acting insulin therapy

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Timing is Everything

Basal Insulin Release

Prandial Insulin Release

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Pathophysiology of Type 1 vs. Type 2 Diabetes

• Type 1– Autoimmune Response, destroying insulin secreting islet cells

(beta cells) of the pancreas– Rapid onset, usually early in life (<30 years)– Total insulin dependence– No insulin resistance– Low insulin supplementation

• Type 2– Progressive insulin resistance in peripheral cells lead to

increased insulin secretion to maintain blood glucose– Insidious onset, usually later in life (>30 years)– Increased insulin demand lead to “burn out” of beta cells of the

pancreas and can lead to total insulin dependence over time– High insulin supplementation

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Type 2 Compensation and Exhaustion

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Goals of Therapy

– Goal• Stabilize Glucose levels within ~ 70-100 mg/dL or

4-7mmol/L

– Strategy• Mimic non-diabetic insulin patterns in patients with

abnormal insulin homeostasis• Increase insulin sensitivity in insulin resistant

patients

– Today’s focus will be on insulin pattern management only

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Ideal Insulin Replacement Strategy

Basal Insulin

Bolus Insulin

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Type 1 Insulin Management

• Goals– Replace Insulin– Prandial (meal time) insulin supplementation– Basal (liver) supplementation

• Strategies– Basal/Bolus Insulin injections

• Rapid acting mealtime insulin• Slow acting basal insulin

– Insulin Pumps• Filled with rapid acting insulin• Vary rate based on actual/anticipated blood glucose levels

• Our talk will focus on Type 2 diabetes

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Tools of the Trade

• Insulin Analogs– Mimic endogenous insulin– Modified kinetics

• Oral Agents– Modify insulin sensitivity– Modify glucose absorption/secretion– Modify insulin secretion

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Type 2 Diabetes Treatment

• Insulin is almost always add on therapy

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Timing is everything – Insulin Preparations

Insulin Onset (hr) Peak (hr) Duration (hr)

Lispro,

Aspart,

Glulisine

<0.25 1-2 3-4

Regular 0.5-1 2-3 3-6

NPH 2-4 4-10 10-16

Glargine 1-2 Flat 24

Detemir 1-2 Flat 12-24

Diabetes Forecast – 2008 Resource Guide (ADA)

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Blood Glucose Management – Monitoring

• So how do we measure efficacy of therapy?– Fasting Blood/Plasma Glucose (FBG/FPG)– Post Prandial Blood Glucose– Glycosylated Hemoglobin A1C (A1C)– Hypoglycemia Incidents

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Diabetes Metrics – Blood Glucose

• Target Range – 70-120 mg/dL– 4-7 mmol/L

• Post Prandial (after meal)– Was bolus adequate?

• Fasting Plasma Glucose– Taken in the morning– Was basal adequate?

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Diabetes Metrics – A1C

• Rough 3 month average of blood glucose• Weighted more heavily to the last month• Good for validating patient’s home

monitoring• Good for estimating post prandial glucose

control in patients only measuring FBG• False “Normal” values can occur in

patients with hypoglycemia and hyperglycemia

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Matching FBG and A1C

A1C% mg/dL6 1357 1708 2059 240

10 27511 31012 345

• 7% A1C = 170mg/dL

• +/-1% A1C = +/- 35mg/dL

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Diabetes Metrics – Hypoglycemic Events

• Events indicate too much insulin

• Daytime suggests bolus may be too high

• Nighttime suggest basal may be too high

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Initiating Insulin Therapy

• GC– Type 2 Diabetic for 10

years is maxed out on Metformin and glyburide

– AM FBG 275, A1C 10%– PCP orders glargine

titration

• Recommendation– Basal insulin (glargine) is

reasonable– Both basal (FBG) and post

prandial (A1C) elevated, more insulin all the time seems like a good idea

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Initiating insulin Therapy

• CC– Type 2 Diabetic for 10 years is

maxed out on Metformin and glyburide

– AM FBG 90, A1C 9.0%– PCP orders glargine titration

• Recommendation– Low FBG suggest basal insulin is

adequate– High A1C suggest post-prandial

glucose is not well controlled– Basal insulin more likely to

precipitate hypoglycemia before target A1C is achieved

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Long Acting Insulin Choices

Insulin Onset (hr) Peak (hr) Duration (hr)

Lispro,

Aspart,

Glulisine

<0.25 1-2 3-4

Regular 0.5-1 2-3 3-6

NPH 2-4 4-10 10-16

Glargine 1-2 Flat 24

Detemir 1-2 Flat 12-24

Diabetes Forecast – 2008 Resource Guide (ADA)

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Longer Acting Insulin Pharmacology

• ToDo

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Longer Acting Insulin Kinetics

NPH

DetemirGlargine

Adapted from: Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in People With Type 1 Diabetes, Heise et al DIABETES 2004;53:1614-1620

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NPH Insulin KineticsNormal Insulin Levels

Adv. DM2 Insulin Production

NPH Insulin Shift

Isolated NPH Curve

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NPH Results

• Provides intermediate duration, delayed insulin peak

• Peak and onset delay are significant

• Intra-patient variability somewhat high

• Good for patients with combination Post Prandial and Basal Hyperglycemia

• Good for nighttime coverage, esp. compared to Regular insulin

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Glargine/Detemir Insulin KineticsNormal Insulin Levels

Reduced Insulin Production

Basal Insulin Shift

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Glargine/Detemir Insulin Results

• Glargine or detemir recommended for patients who experience nocturnal hypoglycemia – VA/DoD clinical practice guideline for the

management of diabetes mellitus (2003)– Long-acting insulin analogues versus NPH insulin

(human isophane insulin) for type 2 diabetes mellitus (Review) Horvath et al (The Cochrane Collaboration 2008)

• No statistically significant difference in Morbidity and Mortality data, i.e. efficacy

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Modifying Insulin Therapy

• CB– Type 2 Diabetic for 3 years– Taking 1000mg Metformin BID, 10mg

glyburide BID, NPH 10units QPM– Complains of daytime hypoglycemia– PCP orders D/C NPH and convert to

glargine 10units QPM– A1C 7%, FBG 120

• Recommendation– NPH only lasts about 10-16 hours,

adding a longer duration insulin at night will increase daytime hypoglycemia

– Consider reducing glyburide (secretalogue) dose

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Modifying Insulin Therapy

• LS– Type 2 Diabetic for 5 years– Taking 1700mg Metformin XR

QPM, 5mg glyburide BID, NPH 10 units QPM

– Complains of nighttime hypoglycemia

– A1C 7%, FBG 60– PCP orders D/C NPH and convert

to detemir 10units QPM• Recommendation

– NPH has a higher incidence of nighttime hypoglycemia vs. detemir

– Switch sounds like a good idea

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Which is Better…

• Published head to head trials with detemir and glargine are limited

• Type 1 & Type 2 each have 1 good study– Detemir demonstrated non-inferiority to glargine– Once daily dosing of glargine and detemir have similar volumes

• Some patients (~50%) will require BID detemir dosing, which typically doubles the daily dose

– There appears to be more injection site issues with detemir vs glargine

– No other efficacy or safety outcomes are clearly better or worse

•Rosenstock, et al A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose lowering drugs in insulin naïve people with type-2 diabetes. Diabetologia 2008: 51;408-416

•Pieber, et al: Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy. Diabetic Medicine 2007; 24:635-642.

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Review of some…“Evidence”

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PREDICTIVE Study

• Commonly sited in second tier journals and review articles

• Very large study 30,000 patients

• Purportedly an observational study comparing detemir vs NPH and/or glargine

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PREDICTIVE Study – biases

• Study sponsored by Novo Nordisk– That’s the detemir folks

• Only subgroup analyses have been published– Cherry picking

• Single arm, observational studies– Translation: improvements from baseline are portrayed as

superior therapy• Participating Physicians paid for participation

– Form of kickback for prescribing MDs• No discussion in power

– Statistics don’t lie: No power calculations, no valid p values, no significant results

• Investigator Bias– All authors are direct employees or are consultants to Novo

Nordisk

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PREDICTIVE Study – Evidence Level

• Observational Studies

• Do not establish cause and effect relationships

• No placebo, active control, or standard of care comparisons

• The published data as been poorly designed, obviously biased, used inappropriate statistical methods

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Switching to Insulin Therapy• NT

– Type 2 diabetes for 8 years– Metformin 500mg BID, Glyburide 10mg

BID– A1C 8%, FBG 170– PCP orders D/C Glyburide 10mg BID

and begin detemir titration based on PREDICTIVE Trial which shows detemir has better control, less weight gain, and less hypoglycemia than glyburide

• Recommendations– PREDICTIVE is an uncontrolled, biased,

observational study and it more marketing than research

– Suggest increase Metformin, continue glyburide, and hold detemir

– Take it to Eleven

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Summary Points

• Insulin detemir and glargine are for basal insulin management with delayed onset and long duration

• Basal insulin therapy is best for Type 1 Diabetics or advanced Type 2 Diabetics who have limited or no endogenous insulin secretion

• Insulin detemir and glargine are equally efficacious to NPH for basal insulin control

• Insulin detemir and glargine have lower incidence of nocturnal hypoglycemia than NPH

• There is no evidence to show either detemir or glargine is superior to the other in side effects or efficacy

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Questions