1 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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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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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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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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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 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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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