Management of Type 2 Diabetes Mellitus: Initiating Insulin Therapy

1. Management of Type 2 Diabetes Mellitus: Initiating Insulin Therapy • Med-Peds Continuity Clinic • Baylor College of Medicine • Anoop Agrawal, M.D.

2. Case One • 50 yo male with diagnosed with Type 2 diabetes three months ago. He has been on Metformin 1000mg bid since diagnosis. A1C was 8.7 at time of diagnosis. • Today: Hgb A1c is 7.3 with a FBS of 165 mg/dl • You are confident he has been compliant with his therapy. What is your next step?

3. Case One • A. No change in therapy, recheck A1c in 3 months • B. Start Glyburide 5mg bid • C. Start Actos 30mg daily • D. Start NPH 10 units qhs

4. Case One • A. No change in therapy, recheck A1c in 3 months • B. Start Glyburide 5mg bid • C. Start Actos 30mg daily • D. Start NPH 10 units qhs B, C or D - all acceptable choices

5. ADA Diabetes Algorithm Diabetes Care, Vol 6, Number 8, August 2006

6. Case One - Clinician Inertia • Initiate therapy with metformin and reevaluate A1c after 3 months. If goal of ≤7% not met, then advance therapy. • It is not necessary to titrate a medication to maximal dosage before adding another agent. • Going above half the max recommended dosage of a sulfonylurea provides little additional benefit. (i.e. glyburide 5mg bid is sufficient) • Similarly, increasing metformin from 2000mg to max of 2550 does little to benefit.

7. Case One - Clinical Inertia • A study out of Kaiser Permanente in California looked at how many patients moved to next level of treatment when A1C was over 8% • On sulfonlyurea - 35% • On metformin - 44% • On two oral agents - 18% • In general, patients spent 5 years with A1C over 8% before decision was made to add insulin!

8. Barriers to Starting Insulin: Patient Driven • Fear of needles/injections and pain • Fear of hypoglycemia • Belief that once one starts insulin, they will soon die • Belief that starting insulin means the “disease has won” • Fear of insulin induced by the provider • “if you don’t start doing X, I’m going to have to put you on insulin”

9. Barriers to Starting Insulin: Provider Driven • Unsure how to start and how to adjust • Fear of promoting vascular complications • Belief that patient compliance will be adversely affected • Fear of patient rejection • Concern for inducing side effects (hypoglycemia, weight gain)

10. Decline in β-cell function: UKPDS 25-30% initial non-responders to OHA 5-20% fail each year by 10-15 yrs, ~100% OHA failure

11. Oral Hypoglycemic Agents: MOA and Efficacy

12. Oral Agents • Sulfonylurea efficacy declines with the progressive diminishing β-cell function. • Metformin and Glitazones continue to provide some benefit throughout the course of the disease especially those with insulin resistance. • In order to adhere to ADA and ACE treatment goals, physicians should consider initiating insulin therapy at the first sign of poor response to oral agents. • In general, patients with A1c >10% need to be on insulin.

13. Insulins and Duration of Action

14. Patient is on glucovance 2.5/500 2 tabs po bid. He has had DM II for 5 years. What is your next course of action? Initiate insulin therapy with BIDS therapy - daytime sulfonylurea and nighttime NPH insulin

15. Case Two • 45 yo female with Type 2 diabetes for the past 5 years. • Current medications: Glipizide 10mg daily and Metformin 1000mg bid • Today: Hgb A1c is 8.5 with a FBS of 150-220 mg/dl over past 2 months in her log book. • What is your next step?

16. Case Two • A. Add on a TZD agent (i.e. Actos) • B. Add on a DPP IV agent (i.e. Januvia) • C. Add on a long acting insulin at bedtime • D. Stop oral drugs and start insulin basal-bolus therapy

17. Case Two • A. Add on a TZD agent (i.e. Actos) • B. Add on a DPP IV agent (i.e. Januvia) • C. Add on a long acting insulin at bedtime • D. Stop oral drugs and start insulin basal-bolus therapy

18. Case Two • Add basal insulin!! Do not add a third oral antidiabetic agent! • Why? • Understand the natural course of diabetes, i.e. the progressive decline of insulin production with time (beta-cell loss) • Understand the relationship between insulin and hepatic glucose production, and its effect on fasting glucose.

19. Bedtime insulin/Daytime Sulfonylurea (BIDS) General rules of thumb: Start with 10 units NPH qhs Administration is usually between 10 pm and midnight.

20. Case Two • First, focus on getting fasting plasma glucose to 70-130 mg/dl. • QHS insulin will suppress hepatic glucose production at overnight, reducing FPG. • In the Treat-to-Target Trial, the addition of nighttime basal insulin to oral agents lowered A1C from 8.6% to 7% in ~10 weeks. • The study also compared NPH vs. glargine and found no difference between NPH and glargine in achieving A1C reduction.

21. Case Two - QHS insulin • In general, the starting dose at bedtime is less important than having a titration algorithm. • Typically, start at 10 units qhs or 0.1 to 0.2 units per kg. • Most patients will end up needing 0.5 to 1.0 units per kg. • Titration can be done every 2-3 days by the patient until FPG reaches near 100-120 mg/dl.

22. Titration of bedtime insulin

23. Initiating Basal Insulin Algorithm • Once FPG at 70-130 mg/dl and A1c still >7% then start assessing pre-meal sugars. • Pre-lunch high: add Reg at breakfast • Pre-dinner high: add NPH at breakfast • Pre-bed high: add Reg at dinner Text Diabetes Care, Vol 6, Number 8, August 2006

24. Insulin + Oral Agents • Pros • Decreased insulin dose • Potential for less hypoglycemia • Less intensive insulin regimens • Cons • Increased number of meds – decreased compliance • Potential for drug interactions • Potentially more costly

25. Case Three: A 56 yo male with glyburide 5mg daily, metformin 1gm bid and NPH insulin 35 units qHS. His A1C is 8%. Below is his blood sugar log. What is your next course of action?

26. Case Three • A. Add Actos 45mg daily • B. Add NPH in the AM and continue qHS • C. Start regular insulin qam and qpm, along with NPH qam and qpm; stop glyburide • D. Start Lantus once daily, stop NPH; continue oral medications.

27. Case Three • A. Add Actos 45mg daily • B. Add NPH in the AM and continue qHS • C. Start regular insulin qam and qpm, along with NPH qam and qpm; stop glyburide • D. Start Lantus once daily, stop NPH; continue oral medications.

28. Case Three • As A1c approaches target levels (<8-8.5%), postprandial glucose contributes more than 50% to value of the A1c. • Use basal insulin to achieve rapid reduction in A1c’s greater than 8.5% • However, to achieve goal of 6.5-7% may require the addition of prandial insulin.

29. ADA Diabetes Algorithm Diabetes Care, Vol 6, Number 8, August 2006

30. Options in basal insulin • Insulin Glargine in place of NPH • Pros: • ease of use (once daily) • 35% lower incidence of hypoglycemia • Cons: • formulary restrictions/cost • NPH equally effective in compliant patients

31. Starting Insulin Only • Normal daily insulin secretion is 0.5 to 0.7 u/kg/day • Hence, starting insulin doses range from 0.3 to 1.0 u/kg/day, with the average being 0.5 to 0.8 u/kg/day. • Factors in choosing 24 hour insulin needs: physical activity level, weight, renal failure, coexisting illness, eating habits

32. Calculating 24-hour insulin needs

33. Insulin Adjustments • Ms. Smith is on NPH 40u/Reg 14u qam, Reg 10u before dinner and NPH 30u qhs. She has reported multiple daytime and nighttime episodes of hypoglycemia. You decide to change NPH to glargine. How do you convert NPH to glargine? • 80% of NPH dose = initial glargine dose

34. Other goals for insulin therapy • Patients who no longer have β-cell function require a Basal-Bolus Insulin Regimen, i.e. NPH bid/glargine qd combined with short acting insulin premeals. • Premix insulins (70/30, 75/25) are more difficult to adjust and hence less popular. Serves as a good option for patients resistant to more than two injections of insulin a day.

35. Common Questions • How often should blood sugar be checked? • At least as often as an injection of insulin is given • Can insulins be mixed (in same syringe)? • NOT with Glargine • Always draw up Short Acting Insulin before intermediate acting • Remember: First draw up clear, then cloudy - short acting insulins are clear, long acting are cloudy (except glargine - is clear)

36. Common Questions • What to do with insulin dose when NPO? • Continue glargine at same dose • Skip Short Acting Insulin • FBG level should not vary if the glargine dose is correct. • If using NPH – pt should take 50% of dose • Skip SAI

37. New Insulin Therapies • Exubera - inhaled insulin • no advantage over injectable insulin • will require monitoring with PFTs • Now off the market due to lack of use • New fast acting agents: glulisine (Apidra) • New intermediate to long acting (basal) insulin: detemir (Levemir)

38. Summary • Oral agents have limited efficacy which will wane over a period of time. • Insulin initiation should be considered in any patient on two oral agents at maximum doses and A1C over 7%. • Combination therapy of an oral agent with insulin is safe and effective. • Choosing and dosing an insulin formulation should take into account the patient’s profile and lifestyle.

39. References • Nathan, DM. et al. Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care Aug 2006;29:1963-1972. • Nelson SE, Palumbo PJ. Addition of Insulin to Oral Therapy in Patients with Type 2 Diabetes. The American Journal of Medical Sciences May 2006;331:257-63. • McMahon G, Dluhy RG. Intention to Treat - Initiating Insulin and the 4-T Study. New England Journal of Medicine Oct 07;357:1759-1761. • Hirsch IB. Insulin Analogues. New England Journal of Medicine Jan 05;352:174-83.