1. Strategies for Choosing 2nd and 3rd Line Agents in Type 2 Diabetes
To Insulin And Beyond!
Strategies for Choosing 2nd and 3rd Line Agents in Type 2 Diabetes
Emily Holm, Pharm.D, BCACP Ambulatory Care Clinical Pharmacist
MN Academy of Physician Assistants
May 11th 2018

2. Objectives Review current guidelines for Type 2 Diabetes
Review classes of medications used for Type 2 Diabetes
Learn various strategies for choosing the appropriate add-on agent for your patient
Apply what we learn to a patient case

3. Patient Case E.G. 51 y.o. White Female Significant PMH
Type 2 Diabetes
Hyperlipidemia
Hypertension
OSA
GERD
Migraines (mild- once every 6 months)
Obesity
UTI (about once a year)
Positive Family History of Type 2 DM and Heart Failure

4. E.G.’s Medications Type 2 DM Hyperlipidemia Hypertension GERD
Metformin 1000mg AM and 1500mg PM w/ meals
Glimepiride 8mg AM w/ breakfast
Type 2 DM
Atorvastatin 40mg at bedtime
Hyperlipidemia
Lisinopril 2.5mg daily
Hypertension
Omeprazole 40mg daily
GERD
Sumatriptan 50mg PRN Migraine
Ondansetron 4mg Q8H PRN N/V associated with Migraine
Migraines
Aspirin 81mg at bedtime
Women’s Multivitamin daily
OTCs

5. E.G. BP: 130/76 mm Hg Ht: 152cm Wt: 112kg BMI: 48.4 kg/m2
A1c: 9.5% (12/2015)
Was 6.8% (08/2015)
Lipids
TC: 166, TG: 154, HDL: 40, LDL 96
SCr: 0.7 mg/dL

6. What should we add next?

7. Let’s Review the Guidelines….

10. Alpha-Glucosidase Inhibitors
Spin the Wheel?!?!?!?
TZDs
SU or Glinides
GLP-1 Agonists
DPP-IV Inhibitors
SGLT2 Inhibitors
Alpha-Glucosidase Inhibitors
Insulins
Note: Synthetic Amylin was not
Included on the wheel

11. Strategies for Choosing Agents
Gather Data
Consider Drug Classes Available
Mechanism of Action
A1c Reduction
Side Effects/Patient Comorbidities
Cost
Patient Preference?
Insurance Formularies

12. What Data Do You Need?? Blood Sugar Logs Ask for 1 to 2 weeks of data
Medications for Type 2 DM act on
Fasting Blood Sugar OR
Post-Prandial Blood Sugar OR
A Mix of Fasting and Post-Prandial
Ask for 1 to 2 weeks of data
AM Fasting Blood Sugar
2 hours after largest meal

13. Medication Chart Class/Drugs
Action on Fasting, Post-Prandial, Or MIXED
Onset of Action15-44
A1c Reduction
Biguanides (Metformin)
Fasting Blood Sugars
Max effect in 2 weeks
1.0%-1.5%3
Sulfonylureas (glipizide, glimepiride, glyburide)
MIXED
Max effect in 1 week
Meglitinides (repaglinide, nateglinide)
Max effect in 1 to 2 weeks %3
DPP-4 Inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin)
Post-Prandial**
%3 (experts feel this range is lower – 0.7%)
GLP-1 Analogs (albiglutide, dulaglutide, exenatide, liraglutide)
Max effect in 4 weeks
SGLT2 Inhibitors (canagliflozin, dapagliflozin, empaglifozin)
Max effect in 1-2 weeks
0.5%-1.0%4

14. Medication Charts Class/Drugs
Action on Fasting, Post-Prandial, or MIXED
Onset of Action15-44
Key Points
Thiazolidinediones (pioglitazone, rosiglitazone)
MIXED
Max effect in 12 weeks
0.5%-1.5%3
Alpha-glucosidase inhibitors (acarbose, miglitol)
Post-Prandial
Max effect in 8 weeks
0.5%-0.8%3
Basal Insulin (glargine, detemir, degludec)
Fasting
Days to 1 week
1.5%-3.5%5
Bolus Insulin (aspart, glulisine, lispro)
MIXED*

15. Biguanide Metformin (Glucophage, Glucophage XR) MOA17 A1c Reduction3
⇩ hepatic glucose production
Improves insulin sensitivity
⇩ intestinal absorption of glucose
A1c Reduction3
1.0%-1.5%

16. Biguanide (Metformin)
Advantages13
No Hypoglycemia
Weight Neutral
Cost is less than $20 per month
Disadvantages13
Diarrhea
Cramping
B12 Deficiency
Lactic Acidosis (rare)

17. Sulfonylureas Glyburide* (Diabeta) Glipizide (Glucotrol, Glucotrol XL)
Glimepiride (Amaryl)
MOA30-32
Stimulates insulin release from Beta Cell in Pancreas
A1C Reduction3
1.0%-1.5%

18. Sulfonylureas Advantages13 Good efficacy (initially)
Cost is less than $10 per month
Disadvantages13
Hypoglycemia
Weight gain
Reduced efficacy over time
Hypoglycemia, especially w/ renal dysfunction
Weight Gain: more with glyburide than with glipizide and glimepiride
Pearls: For eldery – start low and go slow
Discontinue when more complex insulin regimens are started

19. Meglitinides Nateglinide (Starlix) Repaglinide (Prandin) MOA26-27
Stimulates insulin release from Beta Cells in Pancreas
A1c Reduction3
0.5%-1.0%

20. Meglitinides Advantages13
Can be used in place of SU in patients with irregular meals schedules or those who develop late hypoglycemia with SU
Disadvantages13
Hypoglycemia
Weight Gain
Frequent Dosing
Cost is $ per month

21. DPP-4 Inhibitors Alogliptin (Nesina) Linagliptin (Tradjenta)
Saxagliptin (Onglyza)
Sitagliptin (Januvia)
MOA18-21
Inhibits the degradation of endogenous incretins (GLP- 1 & GIP)
A1c Reduction3
0.5%-1.0%
Experts would say A1c reduction is ≤0.7%
Resulting in increased insulin secretion response to elevate glucose, decreased glucagon secretion, slowed GE and increased satiety

22. DPP-4 Inhibitors Advantages13 No hypoglycemia w/ monotherapy
Weight Neutral
Generally well tolerated
Disadvantages13
Renal dosing needed with all except linagliptin
CYP3A4 interactions with saxagliptin and linagliptin
May cause joint pain
May be associated with pancreatitis
Cost is $310-$340 per month

23. GLP-1 Agonists Albiglutide (Tanzeum) Dulaglutide (Trulicity)
Exenatide (Byetta)
Exenatide ER (Bydureon)
Liraglutide (Victoza)
MOA22-25
Enhances glucose dependent insulin secretion
Decreases glucagon secretion during periods of hyperglycemia
Slows gastric emptying and increases satiety
Potential restoration/preservation of beta-cells
A1c Reduction3
1%-1.5%

24. GLP-1 Agonists Advantages13
Low hypoglycemia risk with metformin or monotherapy
Weight Loss
Approved to be used with basal insulin
Lowers Blood Pressure
Disadvantages13
Injection
Nausea
May be associated with pancreatitis
Associated with thyroid cell cancer in rodents
Cost is $325-$480 per month

25. SGLT2 Inhibitors or “flozins”
Canaglifozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
MOA28-30
Blocks glucose reabsorption in kidney, increases glucosuria
A1c Reduction3
0.5%-1.0%

26. SGLT2 Inhibitors or “flozins”
Advantages13
Weight Loss
May reduce blood pressure
Oral
Disadvantages13
Genital fungal infections
UTIs
Increased urination
Hypotension
Increased LDL
Renal adjustments needed
Monitor for hyperkalemia
Decrease BMD (canagliflozin)
Possible ketoacidosis
Cost ~$340+ per month
Mention positive glucose on UA

27. Thiazolidinediones “TZDs”
Pioglitazone (Actos)
Rosiglitazone (Avandia)(REMS program)
MOA33-34
Increases insulin sensitivity in muscle and fat
A1c Reduction3
1.0%-1.5%

28. Thiazolidinediones “TZDs”
Advantages13
Low hypoglycemia risk
Improves HDL
Reduced Triglycerides (pioglitazone)
Pioglitazone is generic –Less than$20 per month
Disadvantages13
Weight Gain
Edema
Congestive Heart Failure
Increased fracture risk
Increases LDL (rosiglitazone)
Possible increase in risk of bladder cancer (pioglitazone)
Avandia was on REMS program and is still a Brand Name

29. Alpha-glucosidase Inhibitors
Acarbose (Precose)
Miglitol (Glyset)
MOA15-16
Slow intestinal carbohydrate digestion/absorption
A1c Reduction3
0.5%-0.8%

30. Alpha-glucosidase inhibitors
Advantages13
Low hypoglycemia risk
Weight neutral
Not absorbed
Works on postprandial glucose
Cost $45-$145 per month
Disadvantages13
INTENSE FLATULENCE
Diarrhea
Only modest effect on A1c
Need for TID dosing

31. Long and Ultra Long-Acting Insulin
Insulin glargine (Lantus® and Toujeo®)
Insulin detemir (Levemir®)
Insulin degludec (Tresiba®)
MOA38-41:
Acts via specific membrane-bound receptors on target tissues to regular metabolism of carbohydrates, protein, and fats.
A1c Reduction5
1.5%-3.5%

32. Insulin Glargine (Lantus®)14
1.1 Hr
Onset
No significant peak
Peak
10.8 to >24 hours
Duration
SubQ once daily*
Administration
100unit/ml in vials (10ml) and pens (3ml)
Formulation
28 days room temp
Stability
$248/ 10ml vial & $372 / box of 5 pens
Cost
Lantus®
Onset
1.1 hr
Peak
No significant peak
Administration
SubQ once daily (some will split the dose)
pH is 4, could be painful
Duration
10.8 to > 24 hours
Formulations
100 units/ ml
Pens and Vials
Stability
28 days at room temp for both pens and vials
Cost
$248/10ml vial
$372/ 5 of 3 ml pen

33. Insulin Glargine (Concentrated) Toujeo®14
Over 6 hours
Onset
No significant peak
Peak
>24 hours
Duration
SUBQ once daily*
Administration
300 units/ml pen (1.5ml)
Formulation
28 days room temp
Stability
$335 / box of 3 pens
Cost
May take at least 5 days to see maximum effect of selected dose. Do not increase the dose more often than every 3 to 4 days. Post marketing data reveals that patients switched from Lantus to Toujeo need their dose increased by about 20%.
1.5ml pen

34. Insulin Detemir (Levemir®)14
1.1 to 2 hours
Onset
No significant peak
Peak
7.6 to >24 hours*
Duration
SUBQ once or twice daily
Administration
100 unit/ml vial (10ml) or pen (3ml)
Formulation
42 days room temp
Stability
$248/ 10ml vial or $372 /box of 5 pens
Cost
* Other sources say the max is 22 hours

35. Insulin degludec (Tresiba®)14
30 to 90 minutes
Onset
Minimal
Peak
42 hours
Duration
SUBQ once daily at any time of the day
Administration
U-100 and U-200 pens (3ml)
Formulation
56 days at room temp
Stability
$443 / box U-100, $532 / box of U-200
Cost
Takes 3 days to reach steady-state
Ensure at least 8 hours between dosing if a dose is missed

36. Long and Ultra-Long Acting Insulin
Advantages13
Effective in all patients
Reduced microvascular complications
No max dose
Disadvantages13
Only effective on fasting blood sugars
Hypoglycemia
Injection
Weight gain
Education/training
Cost

37. Rapid Acting Insulin Insulin lispro (Humalog®)
Insulin aspart (Novolog®)
Insulin glulisine (Apidra®)
MOA35-37
Acts via specific membrane-bound receptors on target tissues to regular metabolism of carbohydrates, protein, and fats
A1c Reduction3
1.5% to 3.5%

38. Rapid Acting Insulin14 Name Humalog® Novolog® Apidra® Onset
mins
10-20 mins
25 mins
Peak
hrs
40 – 50 mins
45-48 mins
Duration
hrs
3 -5 hrs
hrs
Administration
SUBQ w/in 15 before meal or right after
SUBQ w/in 10 mins before meal or right after
SUBQ w/in 15 min before or w/in 20 after starting meal
Formulation
U-100, vials, pens, cartridge U-200 Pen
U-100 vials, pens
U-100 vials and pens
Stability
28 days
Cost
$202/vial, $391 / box of pens
$203/ vial, $392/ box of pens
$203 / vial, $391 /box of pens

39. Rapid Acting Insulin Advantages13 Effective in all patients
No max dose
Meal time and correction coverage
May utilize advanced dosing regimens
Disadvantages13
Hypoglycemia
Multi-injection
Education/training
Cost

40. Mixed Insulin42-45 Novolog 70/30 ® Humalog 75/25 ® Humalog 50/50 ®
Humulin 70/30 ® (NPH/R)
Novolin 70/30® (NPH/R)

41. Mixed Insulin Advantages Twice daily fixed dosing 1 copay
Covers both fasting and post-prandial
Disadvantages
Hypoglycemia middle of the day and middle of the night
Injection
Cost

42. NPH and Regular Use of these are on the rise due to cost Dosing
NPH SUBQ once or 2xday
Regular SUBQ 2 to 3x day
NPH/R 70/30 – SUBQ 2xday
Dose conversion is generally unit to per unit
Administration times may need to change based on regimen

43. New Combinations! Long-Acting Insulin + GLP-1 Xultophy® Soliqua®
Insurance coverage is getting better
Generally have “fail” a basal insulin
Not for patients on doses >50 units of basal
Tresiba + Victoza
Lantus + Adlyxin (Lix –A-Sen-A-Tide

44. Back to the case!! E.G. 51 y.o. White Female Significant PMH
Type 2 Diabetes
Hyperlipidemia
Hypertension
OSA
GERD
Migraines (mild- once every 6 months)
Obesity
UTI (about once a year)
Positive Family History of Type 2 DM and Heart Failure

45. E.G A1c: 9.5% (12/2015) Medications Blood Sugar Log Was 6.8% (08/2015)
Metformin 1000mg AM and 1500mg PM
Glimepiride 8mg AM with breakfast
Blood Sugar Log
Average AM fasting: 145mg/dL
Average 2-hr post-prandial: 299mg/dL

46. Let’s pick some options!
Mixed, but mostly a post-prandial issue
Need ~ 2.5% reduction in A1c
Consider the following
DPP-4
GLP-1
SGLT2
TZD
Insulin (basal, bolus, mixed)

47. What does the patient want?
Willing to try injection*
Wants to lose weight
Wants medication to be effective
Wants to discuss side effects
Wants medication affordable via insurance
Not 4xday injections

48. What could we eliminate?
DPP-4 Inhibitor
A1c reduction is only modest
TZD
Family History of Congestive Health Failure
SGLT2
History of yearly UTI
Basal Insulin
Only effective on fasting blood sugars

49. What is left over? GLP-1 Bolus or Mixed Insulin
Byetta®, Bydureon®*, Tanzeum®*, Trulicity®*, Victoza®
GLP-1
Humalog®, Novolog®, Apidra
70/30, 75/25, 50/50
Bolus or Mixed Insulin
* Denotes once weekly dosing

50. Insurance Formulary Pearls
Find a Pharmacist to HELP YOU!!!
Let Review the following
Formulary Tiers
Medication “Rules”

51. Insurance Formulary Pearls
Drug Tiers
Low cost generics
Tier 1
High cost generics
Tier 2
Formulary Brand
Tier 3
Specialty Drugs
Tier 4

52. Insurance Formulary Pearls
Medication “Rules”
Need to meet certain criteria for coverage
Prior Authorization (PA)
Needs patient to try one or more alternative medications first
Step Therapy (ST)
Only covered if patient is in a specific age range
Age Edit (AE)
Limits the amount of medication the patient can get per fill.
Quantity Limit (QL)

53. Insurance Patient has HealthPartners
PreferredRX Drug Formulary List

54. Plan
Started Victoza® 0.6mg SQ once daily at bedtime x 7 nights, then 1.2mg SQ once daily at bedtime x 7 nights, then 1.8mg SQ once daily at bedtime thereafter.
Copay was $25 per month (w/ copay coupon)
Decrease the glimepiride by 50%
Counseling points
Bedtime Dosing
Increased Satiety
Nausea side effects

55. Follow Up Patient reported mild nausea during the first 3 weeks.
A1c: 7.2% (02/2016)
BP: 122/74 (02/2016)
Wt: 109kg (02/2016)

56. What if? Patient wanted to start Mix Insulin?
Novolog Mix® 70/30
Units/Kg
2/3 dose in the AM w/ breakfast
1/3 dose in PM w/ evening meal
Start at 30 units in the AM and 15 units in the PM
Discontinue Glimepiride
The patient had low risk of UTI and refused injections?
SGLT2 Inhibitor
Jardiance 10mgmg daily (increase to 25mg if needed)
May need to reduce glimepiride dose to prevent hypoglycemia

57. Summary Gather Blood Sugar Data Consider most effective options
Discuss “Pros” and “Cons” of each medication with patient
Drug Formulary/Coupon Cards for cost savings
Follow up

58. Thank You!!!!

59. References
1. AACE/ACE Comprehensive Diabetes Management Algorithm, Endocr Pract. 2015;21 (No.4) Accessed April 14, Cefalu W, Bakris G, Blonde L, et al. ADA-Standards of medical care in diabetes Diabetes Care 2016;S54 Accessed April Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care 2012;35: AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 2016 Published in Endocr Pract.2016;22: Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32: Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient- centered approach. Diabetes Care 2015;38: Handelsman Y, Bloomgarden ZT, Grunberger G, et al. American Association of Clinical Endocrinologists and American College of Endocrinology-Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan – Endo Pract 2015;21(Suppl 1): Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs-FDA and EMA assessment. N Engl J Med 2014;370: PL Detail-Document, Comparison of GLP-1 Agonists. Pharmacist’s Letter/Prescriber’s Letter. December FDA. Invokana and Invokamet (canagliflozin): drug safety communication – new information on bone fracture risk and decreased bone mineral density. September 10, (Accessed April 20, 2016).

60. References
11. FDA. FDA drug safety communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. August 28, gov/drugs/drugsafety/ucm htm. (Accessed April 20, 2015). 12. Udell JA, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care 2015;38: PL Detail-Document, Drugs for Type 2 Diabetes. Pharmacist’s Letter/Prescriber’s Letter. June PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescriber’s Letter. March Acarbose. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Miglitol. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Metformin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Alogliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Linagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Saxagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, 2016.

61. References
21. Sitagliptin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Albiglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Dulaglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Exenatide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Liraglutide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Nateglinide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 14, Repaglinide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Canagliflozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Dapagliflozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Empaglifozin. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Glyburide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Glipizide. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Glimepiride. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Pioglitazone. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Rosiglitazone. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Humalog. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Novolog. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Apidra. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Lantus. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Levemir. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Toujeo. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Tresiba. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Novolog 70/30. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Humalog 75/25. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Humalog 50/50. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, Novolin 70/30. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 20, HealthPartners® PreferredRx 2016 Drug Formulary. Accessed April 20, 2016