1. Diabetes Medication Update: Beyond A1c
James Bennett RPh, FACA, CDE

2. Objectives
Compare and contrast selected medication choices for people with type 2 diabetes including combination injectable products

3. American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care 2017;40(Suppl. 1):S54.

4. American Diabetes Association Standards of Medical Care in Diabetes Diabetes Care 2017;40(Suppl. 1):S54.

5. Diabetes and the Pancreas JAMA 1910
“…..diabetes is not dependent upon the loss of the external secretion of the glands but rather on the absence of some internal secretion which pours directly into the blood- or lymph-stream….it is believed that this secretion is of the nature of a glycolytic ferment whose presence in the blood is necessary for the proper combustion of glucose in the blood.”

6. Newest Insulin products
Longer acting basal
Concentrated basal
Concentrated rapid
Faster acting bolus insulin (in the pipeline)

7. Why do we more insulin formulations ?
WWPD?
Onset of action and duration of action better fit lifestyles of patients
Less variability
Increased adherence
Less hypoglycemia

8. Regular Human Insulin Slow onset of action
Requires inconvenient administration: 30–45 min before meal
Risk of hypoglycemia if meal not consumed
Late postprandial hypoglycemia
Median of 6 hours duration of action

9. Rapid Acting Analogs Faster onset Onset about 15 minutes
More predictable time action curve
Duration about 3-5 hours in most people

10. Variability with NPH Vs. Basal Analogs
The same dose under the similar conditions can vary up to 50% in absorption
NPH has definite but not entirely predictable peaks increasing risk of nocturnal hypoglycemia
Basal analogs
Minimal peak
Glargine 100 unit/ml and detemir up to 24 hour activity
Glargine 300 unit/ml up to 36 hour activity
Degludec up to 42 hour activity

11. Adherence and Dose flexibility
Glargine 300 units/ml
Dose is given once daily but can be administered within a 3 hour window. 1
Degludec 100 or 200 units/ml
Missed doses can given the next day as long as at least 8 hours before next scheduled dose 2
Some evidence points towrd reduced absorption of larger dose volumes so reducing volume may help reduce insulin requirements
Tujueo 450 units per 1.5 ml pen
1. Type 1 diabetes mellitus in adults: high-strength insulin glargine 300 units/ml (Toujeo) NICE Advice, published Oct Accessed Mar 24, Tresiba [package insert]. Bagsvaerd, Denmark: Novo Nordisk; 2015.

12. Less hypoglycemia
….Degludec100 units/ml and 200 units/ml and glargine 300 units/ml are associated with lower risk for nocturnal hypoglycemia compared to other basal insulin formulations.

13. Concentrated Basal Insulin toujeo® (Glargine 300 units/ml)
Advantages: less variability and less nocturnal hypoglycemia
PK (what the body does to the insulin), PD (what the insulin does to the body)
Pearls
May need to up-titrate dose when converting from glargine U-100
Maximum dose per pen 80 units
Missed doses can be given within a three hour window
Titrate every 3-4 days

14. Concentrated Basal Insulin Tresiba® (degludec 100 units/ml and 200 units/ml)
Advantages: less variability and less nocturnal hypoglycemia
PK PD
Pearls
May need to down-titrate when converting from other basal insulins
Maximum dose per pen for U-200 is 160 units and pen contains 600 units of insulin
U100 vs U200 convert unit for unit
Missed doses can be given as long as there are 8 hours before next scheduled dose

15. Concentrated Bolus Insulin Humalog® U-200
Unit per unit dose conversion from U-100 to U-200 (bioequivalent)
PD profiles are essentially the same
Each pen contains 600 units of insulin
Doses from units

16. Fast acting aspart (faster aspart)
Increased absorption rate
Made possible by addition of niacinamide and l-arginine
Lower PPG levels vs plain aspart
Administered 0-2 minutes premeal
Similar PPG levels vs plain aspart when administered after the meal
A1c levels improved with faster aspart
Less hypoglycemia trending toward faster aspart
Dosing
Can be dosed 2 minutes before or 20 minutes after first bite
Type 1 , type 2, pumpers
Diabetes Care, Jones, D.R. Body, B.W. et al online March

17. Help wanted Type 2 Diabetes
Pancreas
beta cells
Muscle
Liver
Fat cells
Kidney
KEY POINT: The kidney contributes to hyperglycemia via increases in renal glucose reabsorption or increased renal gluconeogenesis in type 2 diabetes as compared to the non-diabetic state.
As many of you know, there are defects in function of one or more organs and tissues that lead to the development of impaired glucose tolerance in individuals with type 2 diabetes (T2DM) . The so-called ominous octet includes the liver, muscle, the pancreatic beta cell, the fat cell, the gastrointestinal tract, the pancreatic alpha cell, and the brain. What some of you may not realize is, the kidney is also a key player in this octet.1
In the kidney, glucose reabsorption and the threshold at which glucose spills in the urine are increased in diabetes and contribute to hyperglycemia.2
We also know that, as with the liver, renal glucose production via gluconeogenesis is increased in patients with type 2 diabetes and can contribute to fasting hyperglycemia. 2
 Available medications for reduction of hyperglycemia in T2DM include the following targeted therapies:
Kidney (glucose reabsorption): SGLT2 inhibitors1
Brain (for appetite control): 1 dopamine receptor agonists, serotonin receptor agonists, amylinomimetics 3,4
Liver, muscle and adipocytes: biguanides and thiazolidinediones5
Pancreatic beta cells: sulfonylureas, meglitinides, incretin mimetics, DPP-4 inhibitors5
Pancreatic alpha cells: amylinomimetics , incretin mimetics, DPP-4 inhibitors4.5
Gastrointestinal tract: amylinomimetics , incretin mimetics, colesevalam, alpha-glucosidase inhibitors.4,5
References
DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):
Meyer C, Stumvoll M, Nakkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest. 1998;102(3): Cited by: Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):
Cycloset® (bromocriptine mesylate). Prescribing Information. San Diego, CA: Santarus, Inc.; 2010.
Symlin® (pramlintide acetate) injection. Prescribing Information. San Diego, CA: Amylin Pharmaceuticals, Inc
American Diabetes Association. Standards of medical care in diabetes— Diabetes Care. 2012;35(suppl 1):S11-S63.
Gut
Brain
Alpha cells glucagon Il
1. DeFronzo RA. Diabetes. 2009;58(4): Gerich JE. Diabetic Medicine. 2010; 27:
3. Levin RJ. Am J Clin Nutr. 1994;59(3 suppl):690S-698S.

18. Glucagon-like peptide-1 Receptor Agonists (glp-1 RA)
Exenatide (Byetta®, Bydureon®)
Twice daily and once weekly formulations
Liraglutide (Victoza®)
Once daily
Dulaglutide (Trulicity®)
Once weekly
Albiglutide (Tanzeum®)
Lixisenatide (Adlyxin®)
Once daily 1 hour before the first meal

19. Summary GLP-1 RA Therapies
Multiple actions
Slow gastric emptying
Increase mealtime satiety
Slow glucagon secretion
Stimulate glucose dependent insulin secretion
Effective A1c lowering
Negligible hypoglycemia when used alone
Address postprandial and fasting BG
Weight loss in most cases
May preserve beta cell function
Simplified dosing with longer acting products
Possible CVD risk reduction with selected agents

20. Combination Basal Insulin and GLP-1 RA Degludec/liraglutide (Xultophy®
100 units degludec and 3.6 mg liraglutide per ml
Maximum dose of degludec is 50 units and liraglutide is 1.8 mg
Dosing
Start with 16 units
Titrate by 2 units every 3-4 days

21. Combination Basal Insulin and GLP-1 RA Glargine/lixisenatide (Soliqua®)
100 units glargine and 33 mcg lixisenatide per ml
Maximum dose of glargine is 60 units and lixisenatide 20 mcg
Efficacy
Compared to glargine, improved A1c, weight loss rather than weight gain, and comparable hypoglycemia rates
Dosing
If previously on < 30 units basal start at 15 units
If previously on units of basal start at 30 units
Titrate to target by 2 units weekly

22. Summary of basal insulin/GLP-1 RA combination Therapies
May offer alternative to basal bolus for patients unable to reach target on basal
Robust A1c lowering
Less hypoglycemia than basal/bolus
Less weight gain and possible weight loss compared to basal alone
Simplified once daily dosing
Combination product requiring only one copay

23. Insulin secretagogues
Stimulate pancreas to produce insulin
Sulfonylureas (SFUs): second generation
Glipizide
Glyburide
Glimepiride
Meglitinides (“glinides”)
Repaglinide
Nateglinide
Note: the SFU/meglitinide products are listed last in the AACE hierarchy of treatment choices at every A1c level

24. The one Biguanide: metformin
Reduces hepatic glucose output
Metformin formulations
Immediate release
Extended release
Extended release 24 hour
Oral solution

25. Thiazolidenediones (TZDs)
Increase insulin sensitivity
Agents
Pioglitazone
Rosiglitazone

26. Alpha-glucosidase inhibitors
Slow absorption of carbohydrate in GI tract
Not appreciably systemically absorbed
Agents
Acarbose
Miglitol

27. Miscellaneous agents Bile acid sequestrants: colesevelam
Dopamine agonists: bromocriptine
Amylin mimetics: pramlintide

28. Dipeptidyl peptidase-4 inhibitors (DPP-4 Inhibitors)
Sitagliptin (Januvia®)
Saxagliptin (Onglyza®)
Alogliptin (Nesina®)
Linagliptin (Tradjenta®)
Various combinations with other classes of medications are available

29. Summary of DPP-4 inhibitors
Actions
Stimulate insulin release on a blood glucose dependent basis
Reduce glucagon output
Less robust A1c lowering than some other classes
Little chance for hypoglycemia as monotherapy
Weight neutral

30. Sodium Glucose co-transporter-2 inhibitors (SGLT-2)
Canagliflozin (Invokana®)
Dapagliflozin (Farxiga®)
Empagliflozin (Jardiance®)

31. Summary of sglt-2 inhibitors
Decrease reabsorption of glucose thereby increasing elimination by the kidneys
SGLT-2 action
Lowers A1c
Reduces blood pressure
May help in weight loss
Due to insulin independent action SGLT-2s may be helpful at any stage of type 2 diabetes
Select agents may help reduce CVD risk

32. Two thirds of people with diabetes over 65 die of Cardiovascular disease
American Heart Association. Cardiovascular disease
and diabetes. Accessed July 2017.

33. Cardiovascular disease risk reduction Studies SGLT-2 Inhibitors
Empagliflozin (Farxiga®)
Empa-Reg trial
Reduced risk of cardiovascular death
Canagliflozin (Invokana®)
CANVAS trial
Reduced risk of cardiovascular events
Increased risk of amputations

34. Cardiovascular disease risk reduction Studies completed GLP-1 RA
Liraglutide (Victoza®)
LEADER
Reduced risk of CV death, non fatal MI, non fatal stroke
Semaglutide (not yet marketed)
SUSTAIN-6

35. Summary Many choices allowing customization of therapy
Consider weight gain and hypoglycemia risk
Consider impact on cardiovascular disease
Advance therapy every three months at least
Assess adherence and reinforce importance at every visit

36. James bennett RPh, FACA, CDE
Thanks !
James bennett RPh, FACA, CDE