1. Non-insulin Injectable
Antidiabetics – GLP-1 Receptor
Agonists
Linh Huynh
MCPHS University, PharmD 2016 Candidate
APPE Institutional Rotation - VA West Roxbury
Preceptor: Dr. Susan Jacobson
Date: 03/04/2016

2. Objectives
 Review the pharmacology of GLP-1 Receptor Agonists
 Highlight the advantages and disadvantages of GLP-1 RA
 Compare the products of this class based on a review of
clinical trials
 Discuss the safety and warning issues of GLP-1 RAs

3. Adapted from http://2012.igem.org/wiki/images/thumb/1/13/NTU-Taida-Project-GLP-1.jpg/500px-NTU-Taida-Project-GLP-1.jpg

4. Non-insulin Injectable Antidiabetics - An Overview
Glucagon-like, peptide-1
(GLP-1) agonist or
incretin mimetic
(INJECTION)
- 1% to 1.5% reduction in
A1C
MOA: Stimulation of GLP-1
receptors results in
increased insulin secretion
in response to elevated
blood glucose, decreased
glucagon secretion, slowed
gastric emptying, and
increased satiety. (GLP-1 is
an incretin hormone.)
Generic (Brand) Dose Advantages Disadvantages
Albiglutide (Tanzeum) -
need to be reconstituted
Dulaglutide (Trulicity)
Exenatide (Byetta)
Exenatide extended-release
(Bydureon)
Liraglutide (Victoza)
Albiglutide
INTIAL 30 mg SC once
weekly
Dulaglutide
INITIAL 0.75 mg SC once
weekly
Exenatide
INITIAL: 5 mcg SC BID
Exenatide extended-release
INITIAL: 2 mg SC once
weekly
Liraglutide
INITIAL: 0.6 mg SC once daily
x 1 week, then increase to 1.2
mg SC once daily
- Lack of hypoglycemia
when used as
monotherapy
- Weight loss
- Reduces postprandial
glucose values
- In patients who need
more than one or two
antidiabetes agents,
combination injectable
therapies of basal insulin
and a GLP-1 agonist is
an efficient, emerging
strategy.
- Headache
- Nausea (often transient)
- Diarrhea
- Use with caution in renal
dysfunction
- Avoid in severe renal
impairment (exenatide)
- May be associated with
pancreatitis
- Associated with thyroid
cell cancer in rodents
(check family Hx)
- May be associated with
renal insufficiency

5. What do you think?...
 Would there be hypoglycemic episode when GLP-1 RA
is co-administered with:
 Insulin ?
 Metformin ?
 Glipizide ?

6. What do you think?...
 Would concomitant use of a DDP-4 inhibitor enhance
the effect(s) of GLP-1 RA?

7. Product Appearances
Tanzeum
Trulicity
Byetta
Bydureon
Victoza

8. Comparisons of Products
“GLP-1 receptor agonists: a review of head to-
head clinical studies”
Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and
Metabolism. 2015;6(1):19-28.

9. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and
Metabolism. 2015;6(1):19-28.

10. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism.
2015;6(1):19-28.

11. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism.
2015;6(1):19-28.

12. Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic Advances in Endocrinology and Metabolism.
2015;6(1):19-28.

13. SUMMARY OF THE STUDIES
STUDIES COMPARATORS A1C
CHANGES
WEIGHT
CHANGES
NAUSEA/VOMI
TING
DIARRHEA INJECTION-
SITE RXN
LEAD-6 Byetta
Victoza
Byetta
< Victoza
Similar
reduction
Byetta > Victoza Byetta
< Victoza
Byetta
> Victoza
DURATION-6 Bydureon
Victoza
Bydureon
< Victoza
Bydureon
< Victoza
(reduction)
Bydureon
< Victoza
Bydureon
< Victoza
Bydureon
> Victoza
HARMONY-7 Tanzeum
Victoza
Tanzeum non-
inferior to
Victoza
Tanzeum
< Victoza
(reduction)
Tanzeum
< Victoza
Tanzeum
> Victoza
Tanzeum
> Victoza
AWARD-1 Trulicity 1.5mg
Trulicity 0.75mg
Byetta
Placebo
Trulicity both
doses >
Byetta >
placebo
Trulicity 1.5
> Byetta: not
significant 
Trulicity 0.75
< Byetta:
significant 
Trulicity 1.5 >
Byetta > Trulicity
0.75
Trulicity 1.5 >
Trulicity 0.75
> Byetta
Trulicity 1.5 =
Byetta >
Trulicity 0.75
AWARD-6 Trulicity 1.5
Victoza
Trulicity non-
inferior to
Victora
Trulicity
< Victoza
(reduction)
Trulicity >
Victoza
(nausea), <
(vomiting)
Trulicity =
Victoza
Trulicity
< Victoza

14. SAFETY ISSUES and WARNINGS of GLP-1 RA
Black Box Warning:
 Boxed warning for Risk of Thyroid T-cell Tumor (dose-
related and duration-dependent)
Contraindication:
 Contraindicated in patients with personal or family history of
medullary thyroid carcinoma and in patients with Multiple
Endocrine Neoplasia Type 2
REMS
 To increase awareness of risk for acute pancreatitis and
potential risk of medullary thyroid carcinoma

15. ANTIDIABETIC DRUGS - A SUMMARY
CLASS DRUGS A1C
REDUCTION
EFFECTS ON
WEIGHT
HYPOGLYCEMIC
CONSIDERATION
Alpha-
glucosidase
inhibitor
Acarbose (Precose, others)
Miglitol (Glyset)
0.5 - 1% Weight
neutral
Lack of hypoglycemia when used as
monotherapy
Amylin analog Pramlintide (Symlin) 0.5 - 1% Weight loss Lack of hypoglycemia when used as
monotherapy
Biguanide Metformin (Glucophage, Glucophage XR)
*Available in combination with other classes
1 - 1.5% Weight
neutral
Lack of hypoglycemia when used as
monotherapy
DPP-4 Inhibitor Alogliptin (Nesina)
With metformin (Kazano), pioglitazone (Oseni)
Linagliptin (Tradjenta)
With metformin (Jentadueto), empagliflozin (Glyxambi)
Saxagliptin (Onglyza)
With metformin (Kombiglyze XR)
Sitagliptin (Januvia)
With metformin (Janumet, Janumet XR), simvastatin (Juvisync)
0.5 - 1% Weight
neutral
Lack of hypoglycemia when used as
monotherapy
GLP-1 Agonist
(INJECTION)
Albiglutide (Tanzeum) - need to be reconstituted
Dulaglutide (Trulicity)
Exenatide (Byetta); Exenatide extended-release (Bydureon)
Liraglutide (Victoza)
1 - 1.5% Weight loss Lack of hypoglycemia when used as
monotherapy
Meglitinide Nateglinide (Starlix)
Repaglinide (Prandin, others); With metformin (PrandiMet)
0.5 - 1% Weight gain Hypoglycemia if taken without foods
or severe renal impairment

16. ANTIDIABETIC DRUGS - A SUMMARY (continued)
CLASS DRUGS A1C
REDUCTION
EFFECTS ON
WEIGHT
HYPOGLYCEMIC CONSIDERATION
SGLT-2 Inhibitor Canagliflozin (Invokana), With metformin (Invokamet)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance), With linagliptin (Glyxambi)
0.5 - 1% Weight loss Lack of hypoglycemia when used as
monotherapy
Sulfonylurea–1st
generation
Chlorpropamide (Diabinese, others)
Tolazamide (Tolinase, others)
Tolbutamide (Orinase, others)
1 - 1.5% Weight gain Hypoglycemia more common compared
with second-generation sulfonylureas
Sulfonylurea-2nd
generation
Glyburide (Diabeta, Glynase, Micronase, others)
With metformin (Glucovance)
Glipizide (Glucotrol, Glucotrol XL, others)
With metformin (Metaglip)
Glimepiride (Amaryl, others)
With metformin (Amaryl M), pioglitazone (Duetact),
rosiglitazone (Avandaryl)
1 - 1.5% Weight gain
(glyburide more
than glipizide,
glimepiride)
Hypoglycemia, especially with renal
dysfunction (less with glimepiride versus
glyburide)
Thiazolidinedione
(TZD)
Pioglitazone (Actos)
With metformin (Actoplus Met or Actoplus Met XR), glimepiride
(Duetact), alogliptin (Oseni)
Rosiglitazone (Avandia)
With metformin (Avandamet), glimepiride (Avandaryl)
1 - 1.5% Weight gain Lack of hypoglycemia when used as
monotherapy
Bile acid
sequestrant
Colesevelam (Welchol) 0.5 - 1% Weight neutral Lack of hypoglycemia when used as
monotherapy

17. VA National Formulary (Dec 2015) for Glycemic Control
1.Insulin Aspart
2.Insulin Aspart Protamine/Insulin Aspart (70/30)
3.Insulin Human (NPH/REG) (50/50)
4.Insulin Human (NPH/REG) (70/30)
5.Insulin Human NPH 100U/mL
6.Insulin Human Regular 100U/mL
7.Insulin Long Acting Analog
8.Acarbose
9.Glipizide
10.Metformin
11.Saxagliptin

18. Works Cited/Resources
 Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head clinical studies. Therapeutic
Advances in Endocrinology and Metabolism. 2015;6(1):19-28.
 Trulicity. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 02/11/16; accessed 03/03/16].
http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/5355165#rfs
 Tanzeum. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 02/04/16; accessed 03/03/16].
http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/5100162
 Byetta. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 02/15/16; accessed 03/03/16].
http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/50062
 Victoza. In: Lexi-drugs Online. Hudson (OH): Lexi-Comp, Inc.;[updated 02/15/16; accessed 03/03/16].
http://online.lexi.com.ezproxymcp.flo.org/lco/action/doc/retrieve/docid/patch_f/2144379
 FDA MedWatch. http://www.fda.gov/Safety/MedWatch/
 VA Pharmacy Benefits Management Services. VA National Formulary. Accessed 03/03/16
http://www.pbm.va.gov/nationalformulary.asp

19.  Continuous subcutaneous
exenatide delivery
 Phase III trials
 Once or twice yearly
administration !!!
ITCA 650 (Intarcia Therapeutic, Inc)