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

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

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

Prandial Insulin Release Timing is Everything Prandial Insulin Release Basal Insulin Release

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

Type 2 Compensation and Exhaustion

Goals of Therapy Goal Strategy 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 Today’s focus will be on insulin pattern management only

Ideal Insulin Replacement Strategy Bolus Insulin Basal Insulin

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

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

Type 2 Diabetes Treatment Insulin is almost always add on therapy

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)

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

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?

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

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

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

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

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

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)

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;53:1614-1620

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

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

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

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

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

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

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.

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

Review of some…“Evidence”

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

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

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

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

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

Questions