1. What’s New in Type 2 Diabetes? 2018 Diabetes Updates
Gretchen Ray, PharmD, PhC, BCACP, CDE
Associate Professor, UNM College of Pharmacy
January 28, 2018

2. Objectives
Describe the most recent drug approvals for type 2 diabetes and the cardiovascular outcome data supporting the newer drug classes
Describe the 2018 Treatment recommendations from the American Diabetes Association
Given a patient case, utilize a patient centered approach when selecting pharmacotherapy options for a patient with type 2 diabetes

3. Updated guidelines
Standards of Medical Care in Diabetes Diabetes Care 2018;41(Suppl 1)

4. Diabetes Medications 1960 1995 2000 2005 2010 2015 2016 2017 Insulin
Canagliflozin
Alogliptin
2013
Dapagliflozin
Empagliflozin
Albiglutide
Dulaglutide
Afrezza inhaled
insulin
2014
Diabetes Medications
Saxagliptin
2009
U-300 Glargine
Insulin Degludec
Basaglar
2015
Semaglutide
Ertugliflozin
Fiasp
Admelog
2017
Sitagliptin
2006
Insulin
1922
SUs
1957
Metformin
AGIs
1995
Linagliptin
2011
Glinides
TZDs
1997
Exenatide
Pramlintide
2005
Liraglutide
2010
Plethora of new drugs over last 5 years Exenatide/Byetta-first GLP-1 & incretin
Pramlinitide/Symlin: amylin mimetic, injectable for T1DM and T2DM; will not discuss today
Sitaglilptin/Januvia/Janumet: October 2006, first DPP-4 inhbitor, oral agent
Saxagliptin/Onglyza: July 2009, second DPP-4 inhbitor, oral agent
Liraglutide/Victoza: January 2010, second GLP-1 agonist, injectable once daily formulation
2012
Exenatide LAR
2016
Glargine/lixisenatide
Degludec/liraglutide

5. Types of Insulin Rapid Acting Short Acting-Regular Insulin (R)
Humalog®, Admelog® (lispro) (U-100 and U-200-Humalog® only)
Novolog ®, Fiasp® (aspart)
Apidra ® (glulisine)
Short Acting-Regular Insulin (R)
Novolin® R
Humulin® R
Intermediate Acting-NPH (N)
Novolin® N
Humulin ® N
Long Acting – Basal Insulin
Levemir® (detemir)
Lantus®/Basaglar ® (U-100 glargine)
Toujeo® (U-300 glargine)
Tresiba®(Degludec U-100 and U-200)

6. Insulin Lispro (admelog®): Approved December 2017
First follow-on insulin lispro
Similar to insulin lispro (Humalog®)
Available in U-100 vials and the Solostar® Pen
No dose conversions when switching from other rapid acting insulins

7. Faster acting insulin aspart (fiasp®): Approved 9/2017
Insulin aspart + added niacinamide to speed absorption + L-arginine as a stabilizing agent
Faster aspart vs. insulin aspart in type 1 patients pooled analysis1
5 min earlier onset of insulin exposure
2 x higher early insulin exposure
Offset of exposure and glucose lowering effect min earlier with faster aspart
Inject at start of meal or up to 20 minutes after the start of a meal
Novolog® approved to inject 5-10 minutes before the meal
1. Heise et al. Clin Pharmacokinet 2017;56:551-59

8. Counseling considerations
New concentrations of Glargine U-300, Degludec U-200, and now Insulin Lispro (Humalog®) U-200
Caution patients not to use syringes to draw insulin out of their pens
Different storage criteria of in use pen for each product
New brand names as follow-on insulins
Frequent formulary changes

9. GLP-1 Receptor Agonists

10. GLP-1 Physiology

11. GLP-1 agents
Exenatide (Byetta®) BID dosing timed with meals
Liraglutide (Victoza®) Once daily dosing
Dulaglutide (Trulicity®) Once weekly dosing
Lixisenatide (Adlyxin®)- once daily. FDA approved not not yet available in US as monotherapy
Albiglutide (Tanzeum®)- Will be removed from the market in 2018

12. Exenatide Long Acting: update
2 mg subq once a week
Without regard to meals or time of day
New Bydureon® BCise™ Pen approved- Available in 2018
Single use autoinjector device
Original pen

13. Semaglutide (Ozempic®): Approved December 2017
Titration dose: 0.25 mg once a week
Increase to 0.5 mg after 4 weeks. Max dose 1 mg
0.25/0.5 mg: 1 pen + 6 needles/box
1 mg pen: 2 pens + 4 needles/box
Priming step with each new pen

14. GLP-1 agonist adverse effects/Precautions
Nausea and vomiting –most common AE
Cases of acute pancreatitis
Contraindications/Precautions
eGFR <30, do not use exenatide
Gastroparesis
History of pancreatitis
History of medullary thyroid carcinoma
Multiple endocrine neoplasia syndrome 2
At low titers, the antibodies do not affect the effectiveness of exenatide.
Delays gastric emptying. Counsel patients to take their other meds 1 h before byetta

15. GLP-1 Agonist Benefits Low risk of hypoglycemia Weight loss
Slightly higher risk when used with sulfonylureas or insulin
Weight loss
Potential for once daily or once weekly dosing
Studies have shown addition to a basal insulin can be as effective as starting a pre- meal insulin – see ADA insulin dosing algorithm
Standards of Medical Care in Diabetes Diabetes Care 2018;41(Suppl 1)

16. GLP-1 Agonist/Basal Insulin Combination Pens

17. Insulin glargine & Lixisenatide (Soliqua™ 100/33 Solostar® Pens)
Combination of insulin glargine 100 units/mL and lixisenatide 33 mcg/mL
Available in pen form
1 box = 5 pens = 1500 units
Approved for patients uncontrolled on a basal insulin
Once daily dosing
Dosing:
Patients on <30 units basal insulin: start 15 units of Soliqua™ 100/33
Patients on >30 units basal insulin: start 30 units of Soliqua™ 100/33
Titration is similar to basal insulin alone…increase by 2-4 units/week until fasting glucose <130 mg/dL
Max dose is 60 units
If patient requires >60 units of basal insulin, use a different/individual drugs

18. Insulin Degludec and Liraglutide (Xultophy™ 100/3.6)
100 units Insulin degludec mg liraglutide/mL
Dose range units once a day
Start patients on 16 units once a day
Titrate by 2 units every 3-4 days until fasting glucose at goal
Max dose 50 units (=50 units degludec mg liraglutide)
1 box = 5 pens = 1500 units

19. GLP-1 RA CV Safety Trials

20. Leader: liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results
Evaluated liraglutide vs. placebo + standard of care in patients with type 2 diabetes and high risk of CV disease or with established CV disease
Median follow-up 3.8 years
Primary outcome: first occurrence of death from CV cause, non-fatal MI or non-fatal stroke
Primary outcome occurred in 13.0% liraglutide vs. 14.9% in placebo group (p<0.001 for non-inferiority; p=0.01 for superiority)
FDA indication to reduce risk of CV death, nonfatal MI or nonfatal stroke
13% relative risk reduction
N Engl J Med 2016;375:311-22

21. Secondary Analysis of Renal Outcomes
Leader: liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results
Secondary Analysis of Renal Outcomes
Composite of new onset persistent macroalbuminurea, persistent doubling of serum creatinine level, end-state renal disease, or death due to renal disease
Renal outcome occurred in fewer patients in liraglutide group (268/4668 vs. 337/4672 HR, 0.78; p=0.003)
NEJM 2017;377(9):839-48

22. SUSTAIN-6: Semaglutide CV Safety Trial
Trial design: Patients with DM2 at high risk for CV events were randomized in a 1:1:1:1 fashion to either semaglutide 0.5 mg, semaglutide 1 mg, or matching placebo. They were followed for a median of 2.1 years.
Results
pnoninferiority < psuperiority = 0.02
Primary outcome, CV death/MI/stroke: semaglutide vs. placebo: 6.6% vs. 8.9%, HR 0.74, 95% CI , p < for noninferiority; p = 0.02 for superiority
CV death: 2.7% vs. 2.8%, p = 0.92; all MI: 2.9% vs %, p = 0.12; all stroke: 1.6% vs. 2.7%, p = 0.04
HbA1c at week 104: 7.6% vs. 7.3% vs. 8.3% %
Conclusions
Injectable once a week semaglutide (GLP-1 agonist) was superior to placebo in improving glycemic control and ↓ CV events in high-risk patients with diabetes
Primary outcome
Semaglutide
(n = 1,648)
Placebo
(n = 1,649)
Marso SP, et al. N Engl J Med 2016;375:

23. GLP-1 RA CV Studies demonstrating non-inferiority
ELIXA1-lixisenatide
EXSCEL2- exenatide LAR
Pfeffer MA, et al. NEJM. 2015;373(23):
Holman RR, et al. NEJM Sept 14; epub ahead of print

24. SGLT2 Inhibitors

25. Sodium- glucose co- transporter inhibitors (SGLT2)
SGLT2 INHIBITORS
Sodium- glucose co- transporter inhibitors (SGLT2)
Increase urinary glucose excretion
Sodium glucose co-transporter 2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen.. Inhibiting SGLT2, it reduces reabsorption of filtered glucose and lowers the renal threshold for glucose increasing urinary glucose excretion.

26. SGLT2 InhibitorS Canagliflozin (Invokana™) Dapagliflozin (Farxiga™)
Empagliflozin (Jardiance™)
Ertugliflozin (Steglatro™)- Newly approved
Once daily oral medications
Low risk of hypoglycemia
Weight loss
20 hospitalizations between March 2013 and June 2014 reported in the FDA AERS
Large phase 3 trials have shown no signs of DKA.

27. SGLT2 Inhibitors Side Effects/Precautions Benefits
Female genital mycotic infections
UTI
Increased urination
Hypotension due to volume depletion
Hyperkalemia
Euglycemic ketoacidosis
Rare but recent FDA warning
Possible fracture risk?
Amputation risk with canagliflozin?
Benefits
Once daily oral agents
Insulin independent action
Small weight loss in studies
Low risk of hypoglycemia

28. SGLT2 Inhibitor CV Safety Trials

29. EMPA-REG OUTCOME study
7020 patients with established CVD randomized to empagliflozin or placebo
Primary composite outcome: death from CV cause, nonfatal MI, or nonfatal stroke
10.5% in empagliflozin group vs. 12.1% placebo p=0.04 for superiority
Death from CV causes:
3.7% empagliflozin 5.9% in placebo
38% relative risk reduction
Zinman B, et al. NEJM (22):

30. Empa-reg:CV death, MI and stroke
Patients with event/analyzed
Empagliflozin
Placebo HR
(95% CI)
p-value
3-point MACE
490/4687
282/2333
0.86
(0.74, 0.99)*
0.0382
CV death
172/4687
137/2333
0.62
(0.49, 0.77)
<0.0001
Non-fatal MI
213/4687
121/2333
0.87
(0.70, 1.09)
0.2189
Non-fatal stroke
150/4687
60/2333
1.24
(0.92, 1.67)
0.1638
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Table : 1
Favors empagliflozin
Favors placebo
Zinman B, et al. NEJM (22):

31. Canvas and canvas-R Canagliflozin CV safety and renal outcome study
Included patients >30 years with established ASCVD or >50 years with 2 or more risk factors
Primary outcome: composite of death from CV cause, non-fatal MI or non-fatal stroke
Neil B, et al. NEJM 2017;377(7):

32. Canvas and canvas-R
Neil B, et al. NEJM 2017;377(7):

33. Canvas and canvas-R Renal outcomes
Neil B, et al. NEJM 2017;377(7):

34. Canvas and canvas-R Safety endpoints
Newly identified amputation risk in the canagliflozin group
6.3 vs. 3.4 events/1000 pt years (HR 1.97 [CI ])
Mechanism unknown
Possible increased risk of fracture
Other side effects were similar to other SGLT2 inhibitor trials
Neil B, et al. NEJM 2017;377(7):

35. SGLT2-I CV Safety trials in progress
Dapagliflozin: DECLARE-TIMI58
Estimated completion July 2018
Ertuglifozin: Vertis CV Study
Estimated completion October 2019

36. ADA Management of Hyperglycemia in Type 2 Diabetes
Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

37. Antihyperglycemic Therapy in Adults with T2DM
The first step in the management of newly diagnosed type 2 diabetes is highlighted at the top of the algorithm: initiate lifestyle management, set A1C target, and initiate pharmacotherapy based on A1C at diagnosis.
For those with an initial A1C less than 9%, monotherapy may be considered, while those with an A1C greater than 9% should consider dual therapy, and those with A1C greater than 10%, high blood glucose (>300 mg/dl), or symptoms of hyperglycemia may consider combination injectable therapy, which I’ll detail shortly.
The initial preferred agent remain metformin, though other therapies may be considered if metformin is contraindicated or isn’t tolerated.
If A1C target is not achieved or maintained within 3 months, or at any point, lifestyle management should be reinforced and dual therapy considered.
[SLIDE]
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 37

38. Antihyperglycemic Therapy in Adults with T2DM
Liraglutide or Empagliflozin
Can consider canagliflozin
Starting with dual therapy, the algorithm has been updated this year to incorporate consideration of ASCVD at the point of dual therapy given results of recently published cardiovascular outcome trials.
As noted in the algorithm, in patients who do not have atherosclerotic cardiovascular disease (ASCVD), consider a combination of metformin and any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 receptor agonist, or basal insulin; the choice of which agent to add is based on drug specific effects and patient factors, as highlighted in Table
8.1 which will be highlighted in the next slide.
For patients with ASCVD, add a second agent with evidence of cardiovascular risk reduction after consideration of drug-specific and patient factors.
If A1C target is still not achieved after 3 months of dual therapy, proceed to a three-drug combination. Again, if A1C target is not achieved after ~3 months of triple therapy, proceed to combination injectable therapy. At each step, lifestyle management should be reinforced and medication-taking behavior assessed.
[SLIDE]
Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes Diabetes Care 2018; 41 (Suppl. 1): S73-S85 38

39. Drug factors to consider

40. Drug factors to consider
Class
Efficacy
Hypo
Wt Change
CV Events
Cost
Oral/ SQ
Renal Effects
Other considerations
ASCVD
CHF
DKD
Dosing/
use
SGLT-2 Inh.
Intermed no
loss
Benefit: cana
empa
high
oral
GFR adjustments
Cana risk of amputation & bone fx
GU infection
Volume depletion
hypotension
GLP-1 RA
High
Liraglutide benefit
neutral
Benefit: liraglutide
Exenatide CI if GFR<30
FDA Box warning: thyroid C-cell tumors
GI side effects
Injection site reaction
Pancreatitis?
Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

41. Approach to starting and adjusting insulin in type 2 diabetes
Approach to starting and adjusting insulin in type 2 diabetes. FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. Diabetes Care, 2015;38:
References
American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care 2014;37(suppl 1):S27–S28
Blonde L,MerilainenM, Karwe V, Raskin P; TITRATE Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets the TITRATE study. Diabetes Obes Metab 2009;11:623–631
Inzucchi SE, Bergenstal RM, Buse JB, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379 41

42. Considerations when adding on therapy to metformin
Choice is based on patient and drug characteristics
Use ADA algorithm and knowledge of pharmacology, cost, patient preference, and side effect profile
Consider insulin +/- other agents in newly diagnosed patients with glucose >300 and/or A1C >10% or symptomatic
Consider initiating dual therapy in newly diagnosed patients with A1C >9%
In patients with diabetes and established ASCVD, empagliflozin or liraglutide should be incorporated as they have been shown to reduce CV and all-cause mortality
Canagliflozin can also be considered
Standards of Medical Care in Diabetes. Diabetes Care 2018;41(Suppl 1)

43. Questions