Management of Type 2 Diabetes Mellitus

1
Management of Type 2 Diabetes Mellitus

• Med-Peds Continuity Clinic
• Baylor College of Medicine
• Anoop Agrawal, M.D.

2
Case One

• 50 yo male diagnosed with Type 2 diabetes one and
  a half years ago. He has been on Glyburide 5 mg
  bid for the past three months. A1C was 9.0 three
  months ago. He returns for f/u.
• Today Hgb A1c is 8.3 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. Continue Glyburide 5mg bid and recheck A1C in
  3 months
• B. Increase Glyburide to 10mg bid
• C. Add on Metformin 500 mg bid
• D. Increase Glyburide to 10 mg bid and add on
  Metformin 500 mg bid

4
Case One

• A. Continue Glyburide 5mg bid and recheck A1C in
  3 months
• B. Increase Glyburide to 10mg bid
• C. Add on Metformin 500 mg bid
• D. Increase Glyburide to 10 mg bid and add on
  Metformin 500 mg bid

5
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!

6
Case One - Clinical Inertia

• Dosage of an oral agent should be increased every
  4 to 8 weeks until fasting and postprandials are
  at target.
• It is not necessary to titrate a medication to
  maximal dosage before adding a second agent.
• Going above half the max recommended dosage of a
  sulfonylurea provides little additional benefit.
• Similarly, increasing metformin from 2000mg to
  max of 2550 does little to benefit.

7
Decline in ß-cell function UKPDS
100
25-30 initial non-responders to OHA 5-20 fail
each year by 10-15 yrs, 100 OHA failure
50
Beta-cell function ()
0
-10 -5 0 5 10
Years from diagnosis
8
Oral Hypoglycemic Agents MOA and Efficacy
Agent MOA ? A1c
Sulfonylureas increase insulin production from ß cells 1 to 2
Biguanides inhibits hepatic glucose production increases insulin sensitivity up to 2
Thiazolidinedione increase insulin sensitivity 0.8 to 1
Alpha-glucosidase inhibitors inhibit glucose absorption 0.5 to 1
9
Oral Agents

• Sulfonylurea efficacy declines with the
  progressive diminishing ß-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 gt10 need to be on
  insulin.

10
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 dont start doing X, Im going to have to
  put you on insulin

11
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)

12
Insulins and Duration of Action
13
Case Two

• 45 yo female with Type 2 diabetes for the past 5
  years.
• Current medications Actos 30mg daily and
  Metformin 850mg tid
• Today Hgb A1c is 9.3 with a FBS of 180-250 mg/dl
  over past 2 months in her log book.
• You are confident she has been compliant with her
  therapy. What is your next step?

14
Case Two

• A. Add on a sulfonylurea
• B. Add on a DPP IV agent
• C. Stop Actos and add on sulfonylurea
• D. Add on a long acting insulin at bedtime
• E. Stop oral drugs and start insulin basal-bolus
  therapy

15
Case Two

• A. Add on a sulfonylurea
• B. Add on a DPP IV agent
• C. Stop Actos and add on sulfonylurea
• D. Add on a long acting insulin at bedtime
• E. Stop oral drugs and start insulin basal-bolus
  therapy

16
Case Two

• Add basal insulin!! Do not add a third oral
  antidiabetic agent!
• Why?
• Understand the natural course of diabetes, i.e.
  the progressive declince of insulin production
  with time
• Understand the relationship between insulin and
  hepatic glucose production, and its effect on
  fasting glucose.

17
Case Two

• First, focus on getting fasting plasma glucose to
  100 mg/dl.
• QHS insulin will suppress hepatic glucose
  production at overnight, reducing FPG.
• In the Treat-to-Target trial (4-T 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.

18
Bedtime insulin/Daytime Sulfonylurea (BIDS)
General rules of thumb Start with 10 units NPH
qhs Administration is usually between 10 pm and
midnight.
19
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.

20
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

21
Titration of bedtime insulin
FPG values in preceding 2 days increase in insulin dosage (U/day)
180 mg/dl 8
140-180 mg/dl 6
120-140 mg/dl 4
100-120 mg/dl 2
22
Pros/Cons of 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

23
Case Three A 56 yo male with glyburide 5mg bid,
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?
24
Case Three

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

25
Case Three

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

26
Case Three

• As A1C approaches target levels (lt8-8.5),
  postprandial glucose contributes more to A1C.
• Use basal insulin to achieve rapid reduction in
  A1Cs greater than 8.5
• However, to achieve goal of 6.5-7 requires the
  addition of prandial insulin.

27
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

28
Calculating 24-hour insulin needs
Physical Activity Level Normal Weight Obese
High 0.3 U/kg 0.5 U/kg
Moderate 0.4 U/kg 0.6 U/kg
Low 0.5 U/kg 0.8 U/kg
Coexisting Illness (CKD) Subtract 0.2 U/kg Subtract 0.2 U/kg
Big eater eating habits Add 0.1 U/kg Add 0.1 U/kg
29
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

30
Other goals for insulin therapy

• Patients who no longer have ß-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, 50/50) 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.

31
Common Patient Questions

• Can insulins be mixed (in same syringe)?
• NOT with Glargine (though at TCH this is
  changing)
• 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)

32
Common Patient 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

33
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)

34
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 7-8.
• Combination therapy of an oral agent with insulin
  is safe and effective. (except regular insulin
  sulfonylurea)
• Choosing and dosing an insulin formulation should
  take into account the patients profile and
  lifestyle.

35
References

• Nelson SE, Palumbo PJ. Addition of Insulin to
  Oral Therapy in Patients with Type 2 Diabetes.
  The American Journal of Medical Sciences May
  2006331257-63.
• McMahon G, Dluhy RG. Intention to Treat -
  Initiating Insulin and the 4-T Study. New
  England Journal of Medicine Oct 073571759-1761.
• Hirsch IB. Insulin Analogues. New England
  Journal of Medicine Jan 05352174-83.