Non-insulin Injectable Antidiabetics – GLP-1 Receptor Agonists

Linh HuynhMCPHS University, PharmD 2016 CandidateAPPE Institutional Rotation - VA West RoxburyPreceptor: Dr. Susan Jacobson Date: 03/04/2016

ObjectivesReview the pharmacology of GLP-1 Receptor

AgonistsHighlight the advantages and disadvantages of

GLP-1 RA Compare the products of this class based on a

review of clinical trialsDiscuss the safety and warning issues of GLP-1 RAs

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

Non-insulin Injectable Antidiabetics - An OverviewGlucagon-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)

AlbiglutideINTIAL 30 mg SC once weekly

DulaglutideINITIAL 0.75 mg SC once weekly

ExenatideINITIAL: 5 mcg SC BID

Exenatide extended-releaseINITIAL: 2 mg SC once weekly

LiraglutideINITIAL: 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

What do you think?... Would there be hypoglycemic episode when

GLP-1 RA is co-administered with: Insulin ?Metformin ?Glipizide ?

What do you think?... Would concomitant use of a DDP-4 inhibitor

enhance the effect(s) of GLP-1 RA?

Product AppearancesTanzeum

Trulicity

Byetta

Bydureon

Victoza

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.

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.

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.

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.

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.

SUMMARY OF THE STUDIES STUDIES COMPARATOR

SA1C CHANGES

WEIGHT CHANGES

NAUSEA/VOMITING

DIARRHEA INJECTION-SITE RXN

LEAD-6 Byetta Victoza

Byetta < Victoza

Similar reduction

Byetta > Victoza

Byetta < Victoza

Byetta> Victoza

DURATION-6 BydureonVictoza

Bydureon< Victoza

Bydureon< Victoza (reduction)

Bydureon< Victoza

Bydureon < Victoza

Bydureon> Victoza

HARMONY-7 TanzeumVictoza

Tanzeum non-inferior to Victoza

Tanzeum< Victoza (reduction)

Tanzeum< Victoza

Tanzeum> Victoza

Tanzeum> Victoza

AWARD-1 Trulicity 1.5mgTrulicity 0.75mgByettaPlacebo

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 1.5Victoza

Trulicity non-inferior to Victora

Trulicity< Victoza(reduction)

Trulicity > Victoza (nausea), < (vomiting)

Trulicity = Victoza

Trulicity < Victoza

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

REMSTo increase awareness of risk for acute pancreatitis

and potential risk of medullary thyroid carcinoma

ANTIDIABETIC DRUGS - A SUMMARYCLASS DRUGS A1C

REDUCTIONEFFECTS 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 reconstitutedDulaglutide (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

ANTIDIABETIC DRUGS - A SUMMARY (continued)CLASS DRUGS A1C

REDUCTIONEFFECTS 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

VA National Formulary (Dec 2015) for Glycemic Control

1.Insulin Aspart2.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/mL6.Insulin Human Regular 100U/mL7.Insulin Long Acting Analog8.Acarbose9.Glipizide10.Metformin11.Saxagliptin

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

Continuous subcutaneous exenatide delivery

Phase III trialsOnce or twice yearly

administration !!!

ITCA 650 (Intarcia Therapeutic, Inc)