Basal Insulin Therapy

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Basal Insulin Therapy

• Ted D. Williams
• PharmD Candidate
• OSU College of Pharmacy

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Cases

• Initiating Insulin Therapy
• Modifying Insulin Therapy
• Switching to Insulin Therapy
• FBG
• A1C

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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
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 (lt30 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 (gt30
  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 70-120 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
• Todays focus will be on insulin pattern
  management only

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Ideal Insulin Replacement Strategy
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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 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
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 patients 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

• 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
Diabetes Forecast 2008 Resource Guide (ADA)
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Longer Acting Insulin Kinetics
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 2004531614-1620
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NPH Insulin Kinetics
Normal Insulin Levels
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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 Kinetics
Normal 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
  51408-416
• Pieber, et al Comparison of insulin detemir and
  insulin glargine in subjects with Type 1 diabetes
  using intensive insulin therapy. Diabetic
  Medicine 2007 24635-642.

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Cost Comparison

• National PBM Drug Monograph, Insulin detemir
  (Levemir),VHA Pharmacy Benefits Management
  Strategic Healthcare Group and Medical Advisory
  Panel

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Review of someEvidence
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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
• Thats 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 dont 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