Post on 14-Jan-2017
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)