1. Ted D. Williams PharmD Candidate OSU College of Pharmacy
Basal Insulin Therapy
Ted D. Williams
PharmD Candidate
OSU College of Pharmacy

2. Cases Initiating Insulin Therapy Modifying Insulin Therapy
Switching to Insulin Therapy
FBG
A1C

3. Objectives Pathophysiology Kinetics of insulin analogs
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

4. Prandial Insulin Release
Timing is Everything
Prandial Insulin Release
Basal Insulin Release

5. Pathophysiology of Type 1 vs. Type 2 Diabetes
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

6. Type 2 Compensation and Exhaustion

7. Goals of Therapy Goal Strategy
Stabilize Glucose levels within ~ 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

8. Ideal Insulin Replacement Strategy
Bolus Insulin
Basal Insulin

9. 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

10. Tools of the Trade Insulin & Insulin Analogs Oral Agents
Mimic endogenous insulin
Modified kinetics
Oral Agents
Modify insulin sensitivity
Modify glucose absorption/secretion
Modify insulin secretion

11. Type 2 Diabetes Treatment
Insulin is almost always add on therapy

12. Timing is everything – Insulin Preparations
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
Flat 24
Detemir
12-24
Diabetes Forecast – 2008 Resource Guide (ADA)

13. 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

14. Diabetes Metrics – Blood Glucose
Target Range
mg/dL
4-7 mmol/L
Post Prandial (after meal)
Was bolus adequate?
Fasting Plasma Glucose
Taken in the morning
Was basal adequate?

15. 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

16. Matching FBG and A1C
7% A1C = 170mg/dL
+/-1% A1C = +/- 35mg/dL

17. Diabetes Metrics – Hypoglycemic Events
Events indicate too much insulin
Daytime suggests bolus may be too high
Nighttime suggest basal may be too high

18. Initiating Insulin TherapyGC
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

19. Initiating insulin TherapyCC
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

20. Long Acting Insulin Choices
Onset (hr)
Peak (hr)
Duration (hr)
NPH
2-4
4-10
10-16
Glargine
1-2
Flat 24
Detemir
12-24
Diabetes Forecast – 2008 Resource Guide (ADA)

21. Longer Acting Insulin Kinetics
NPH
Glargine
Detemir
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:

22. NPH Insulin Kinetics Normal Insulin Levels Adv. DM2 Insulin Production
Isolated NPH Curve
NPH Insulin Shift

23. 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

24. Glargine/Detemir Insulin Kinetics
Normal Insulin Levels
Reduced Insulin Production
Basal Insulin Shift

25. 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

26. Modifying Insulin TherapyCB
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 hours, adding a longer duration insulin at night will increase daytime hypoglycemia
Consider reducing glyburide (secretalogue) dose

27. Modifying Insulin TherapyLS
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

28. 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;
Pieber, et al: Comparison of insulin detemir and insulin glargine in subjects with Type 1 diabetes using intensive insulin therapy. Diabetic Medicine 2007; 24:

29. Cost Comparison
National PBM Drug Monograph, Insulin detemir (Levemir®),VHA Pharmacy Benefits Management Strategic Healthcare Group and Medical Advisory Panel

30. Review of some…“Evidence”

31. 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

32. 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

33. 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

34. Switching to Insulin Therapy
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

35. 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

36. Questions