Transcript DPP-4 Inhibitors

WAYNE STATE UNIVERSITY
COLLEGE OF PHARMACY & HEALTH SCIENCES
JANUARY 13, 2016
The Evolving Armamentarium
for Type 2 Diabetes:
Clinical Assistant
Professor,
Department of
Pharmacy Practice
Ambulatory Care
Specialist,
Health Centers
Detroit
Medical Group
Incorporating New Classes
in the Treatment of
Our Patients
METFORMIN
INSULIN
ALPHA GLUCOSIDASE INHIBITORS
GLP-1 RAs
THIAZOLIDINEDIONES
MEGLITINIDES
SULPHONYLUREAS
SYNTHETIC AMYLIN
ANALOG
DPP-4 INHIBITORS
1921
1930’s
INSULIN
1950’s
1980’S
1st BIOSYNTHETIC
INSULIN
1990’S
2000
2001-10
2010-15
FUTURE?
1st BASAL INSULIN
SGLT-2
INHIBITORS
AFREZZA
TOUJEO
DEGLUDEC
THE DECADES OF DIABETES
Objectives
Describe novel physiologic targets for the treatment of
diabetes
Compare and Contrast the pharmacology, safety & efficacy of
3 new classes:
• Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RAs)
• Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors)
• Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2 Inhibitors)
Construct a diabetes treatment regimen that incorporates
these new classes in a given patient scenario
Pathogenesis of T2DM: The Ominous Octet
Kruger DF, et al. Diabetes Educ 2010; 36: 44S.
Case: Part I
HP is a 67 yo female who presents to the pharmacist-run diabetes clinic
for a follow-up. She is currently taking Metformin ER 1g 2 tablets once
daily, and Glipizide XL 10mg 1 tablet once daily for her diabetes. She
reports being rather discouraged today as she has been trying to lose
weight and has not been successful. Current weight = 190 lbs, Height =
5’3”
PMH: Diabetes x 1 year, HTN, Dyslipidemia, Osteoporosis
Point of Care A1c today = 8.6%
Which of the following new classes is NOT associated with weight
loss:
a. Glucagon-Like Peptide 1 Receptor Agonists (GLP-1 RA)
b. Dipeptydil Peptidase-4 (DPP-4) Inhibitors
c. Sodium Glucose Co-Transporter 2 (SGLT-2) Inhibitors
Place in Therapy: ADA Position Statement
Inzucchi et al.
What is the role of
Glucagon-Like Peptide-1?
Incretin Effect
Control Subjects
T2DM
- Oral Glucose
- IV Glucose
a- p≤0.05
Nauck et al. Diabetologia 1986; 29:46-52
Decreased GLP-1 Levels in T2DM
Toft-Nielsen et al. J Clin Endocrinol Metab. 2001, 86:3717-23
Endogenous GLP-1
? Neuroprotection
Appetite
Brain
Stomach
Heart
Gastric emptying
? Cardioprotection
GLP-1
Pancreas
? Cardiac output
*
Insulin secretion
GI tract
Glucagon secretion
? β-cell proliferation
Liver
Glucose production
*
? β-cell apoptosis
Muscle
? Insulin sensitivity
Drucker DJ. Cell Metab. 2006;3:153-165
Limitations of Human GLP-1
DPP-IV
His
Ala
Glu
Gly Thr Phe Thr Ser Asp
Val
Ser
Lys
Ala
Ala
Gln
Gly Glu Leu
Tyr
Ser
Glu
Phe
Ile
Ala
Trp Leu Val Lys Gly Arg Gly
Mentlein R. Eur J Biochem. 1993;214:829-836
GLP-1 RECEPTOR
AGONISTS
BYETTA
VICTOZA
BYDUREON
TANZEUM
TRULICITY
(EXENATIDE)
(LIRAGLUTIDE)
(EXENATIDE EXTENDED RELEASE)
(ALBIGLUTIDE)
(DULAGLUTIDE)
Benefits of
GLP-1 RAs
Weight loss
Low risk of
hypoglycemia
A1c Efficacy
Weekly Dosing
β-cell
preservation?
Adverse Effects
Nausea
Vomiting
Diarrhea
Headache
Injection site
reactions
Chemical Structures of GLP-1 RAs
BYETTA
(Exenatide)
53% Homology
Gila monster
saliva
VICTOZA
(Liraglutide)
97% Homology
C-16 Fatty
Acid Chain
TANZEUM
(Albiglutide)
97% Homology
Dimer fused
to Albumin
BYDUREON
(Exenatide ER)
53% Homology
Microsphere
technology
TRULICITY
(Dulaglutide)
90% Homology
Linked to
modified IgG
Pharmacology
BYETTA
Exenatide
VICTOZA
Liraglutide
BYDUREON
Exenatide
ER
TANZEUM
Albiglutide
TRULICITY
Dulaglutide
BID
QD
QW
QW
QW
Dosage
5 & 10 mcg
0.6, 1.2 &
1.8 mg
2 mg
30 & 50 mg
0.75 & 1.5 mg
Half-life
2.4 hours
~ 13 hours
~ 2 weeks
Renal
Excretion

-

-
-
Renal Dosing
CrCL 30-50
CAUTION
-
CAUTION
-
-
Renal Dosing
CrCl < 30
Not
recommended
CAUTION
Not
recommended
Dosing
Frequency
~ 5 days
CAUTION
Administration
BYETTA
Exenatide
VICTOZA
Liraglutide
BYDUREON
Exenatide ER
TANZEUM
Albiglutide
TRULICITY
Dulaglutide
BID
QD
QW
QW
QW
30 days
30 days
4 weeks
4 weeks
4 weeks
 60 mins.
-
-
-
-
Needle Gauge
29-31 G
32 G
23 G
29 G
29 G
Reconstitution
-
-


-
Pre-Injection
Waiting Time
-
-
-
15-30 minutes
Dosing
Frequency
Room Temp.
Food
AUTOINJECTOR
Patient Education
Nausea & Vomiting
•
•
•
•
•
Eat slow and stop when full
Smaller meals
Avoid overeating
Byetta: take closer to meal time
Severe with Abdominal pain
Don’t expect rapid BG lowering
Changes in urination
•
urine color/frequency/amount, unexplained extremity swelling
A1c
PPBG
QW
BID
DURATION-1
&
DURATION-5
Weight
FBG
QW
N/V
Injection
Reactions
BID
QW
Head-to-Head Studies
vs. Victoza:
A1c
BYETTA
BYDUREON
TANZUEM
TRULICITY
- 0.33 %
BYETTA: - 0.79
[p<0.0001]
VICTOZA: - 1.2
LEAD-6
(n=464)
DURATION-6
BYDUREON: - 1.28
- 0.21 %
VICTOZA: - 1.48
[p=0.02]
(n=911)
HARMONY-7
(n=841)
TANZEUM: - 0.78
VICTOZA: - 0.99
AWARD-6
(n=599)
- 0.21 %
[p=0.0846, Non-Inferiority]
TRULICITY: - 1.42
VICTOZA: - 1.36
- 0.06 %
[p<0.0001, Non-Inferiority]
Head-to-Head Studies
vs. Victoza:
Weight
BYETTA
BYDUREON
TANZUEM
TRULICITY
- 0.38 kg
BYETTA: - 2.87
[p=0.2235]
VICTOZA: - 3.24
LEAD-6
(n=464)
DURATION-6
BYDUREON: - 2.68
- 0.9 kg
VICTOZA: - 3.57
[p=0.0005]
(n=911)
HARMONY-7
(n=841)
TANZEUM: - 0.64
VICTOZA: - 2.16
AWARD-6
(n=599)
- 1.55 kg
[p<0.0001]
TRULICITY: - 2.90
VICTOZA: - 3.61
- 0.71 kg
[p=0.011]
Additional Results
•
•
•
•
•
FBG vs PPBG
GI AEs
Injection Site Reactions
CV Risk Factors: BP, Cholesterol, HR
Hypoglycemia
Glucose-Dependent Mechanism
Caution:
Sulfonylureas
&
Insulin
www.sciencedirect.com
GLP-1 RAs & Insulin
Benefits of Combination:
• Weight loss / Minimize weight gain
• Minimize hypoglycemia
Dosing Recommendations:
• Reduce insulin dose by 20%
Pipeline:
• LixiLan (Lixisenatide and Glargine) - Phase III
Additional Precautions
• Altered/Worsening Kidney Function
• Pancreatitis
• Thyroid C-Cell / Medullary Thyroid Carcinoma (MTC)
• Black Box Warning
• CI: Multiple endocrine neoplasia syndrome type 2
• CI: Personal or FHx of medullary thyroid carcinoma
• REMS
• Pancreatitis & MTC
Case: Part II
Last month HP was started on Byetta 5 mcg BID and is at the
pharmacy for today for a refill. She is unhappy that the numbers on
her meter are still “high”, however, she admits that she doesn’t
always take her medications during the week. She takes care of her
3 grandchildren from Monday to Friday and misses 2-3 doses per
week, as these days are very hectic. HP injects her Byetta
immediately prior to a meal. She reports nausea which is
bothersome, however, she is happy to have seen some weight loss.
In addition to counseling her on compliance, which of the following is
the most appropriate recommendation at this time?
a.
b.
c.
d.
Increase the dose of Byetta
Instruct her to inject Byetta 60 minutes prior to meals
Change to Victoza (Liraglutide)
Change to Trulicity (Dulaglutide)
GLP-1 RAs: Clinical Pearls
Benefits
• Efficacy: A1c ~1-1.5%
• PPBG > FBG: Exenatide
• FBG > PPBB: Longer acting agents
•
•
•
•
Weight Loss
Low risk of hypoglycemia
Insulin dose reduction
Long Acting: Compliance,
less N/V/D, Use in CKD
• Delayed disease progression?
• Additional benefits?
Concerns
• FDA Warnings: Kidney failure,
pancreatitis, thyroid c-cell
cancer
• Prescriber unfamiliarity
• GI Adverse Effects
• Nodules
• Interactions
• Gastroparesis
• Injectable
• Cost
What is the role of
DDP-4?
Limitations of Human GLP-1
DPP-IV
His
Ala
Glu
Gly Thr Phe Thr Ser Asp
Val
Ser
Lys
Ala
Ala
Gln
Gly Glu Leu
Tyr
Ser
Glu
Phe
Ile
Ala
Trp Leu Val Lys Gly Arg Gly
Mentlein R. Eur J Biochem. 1993;214:829-836
DPP-4 INHIBITORS
JANUVIA
(SITAGLIPTIN)
ONGLYZA
(SAXAGLIPTIN)
TRADJENTA (LINAGLIPTIN)
NESINA
(ALOGLIPTIN)
MOA: DPP-4 Inhibitor vs. GLP-1 RA
GLP-1 RA
↑ Glucose-dependent insulin secretion
↓ Glucagon secretion
↓ Plasma glucose levels
↓ Rate of gastric emptying
↑ Satiety
↓ Food intake
DPP-IV Degredation
Duration of action






Long
DPP-4
Inhibitor



Intermediate
Benefits of
DPP-4 Inhibitors
Low risk of
hypoglycemia
Weight neutral
Once daily
ORAL
Well tolerated
Adverse Effects
URI
Nasal pharyngitis
Headache
Hypersensitivity
Pancreatitis
Pharmacology
JANUVIA
(SITAGLIPTIN)
ONGLYZA
(SAXAGLIPTIN)
TRADJENTA
(LINAGLIPTIN)
NESINA
(ALOGLIPTIN)
25, 50, 100 mg
2.5 & 5 mg
5 mg
6.25, 12.5, 25 mg
12.4
2.5
> 100
21
(active metabolite)
Dosing Frequency
Dosage
Half-life (hours)
(active metabolite= 3.1)
Metabolism
CYP3A4/5
Not extensively
metabolized
CYP2D6/3A4
Renal
Renal
Bile
Renal
Dose Adjustment
in CKD/ESRD


--

Combination
Products




Majority of
Elimination
Not extensively
metabolized
Severe Arthralgia
• Substantial reduction in prior level of activity
• 33 cases (2006 – 2013)
• 10 Hospitalizations
• 8 cases re-challenged
• Symptom onset: 1 month – 1 year
• Does the pain go away?
HEART FAILURE?
CARDIOPROTECTIVE?
Neutral effect on AllCause and CV
mortality
SAVOR
(Saxagliptin)
TECOS
(Sitagliptin)
EXAMINE
(Alogliptin)
↑ Heart Failure
Hospitalizations
Further Evaluation…
Cardiovascular Effects?
Case: Part III
HP is now on Metformin, Glipizide and Trulicity (Dulaglutide)
for her diabetes. One year later, her A1c is 7.6%. Her PCP
wants to add a DPP-4 inhibitor and asks you for your
recommendation.
Which of the following is most the most appropriate
recommendation?
a. Add Januvia (Sitagliptin)
b. Add Onglyza (Saxagliptin)
c. Add Nesina (Alogliptin)
d. A DPP-4 Inhibitor will not be beneficial for this patient
DPP-4 Inhibitors: Clinical Pearls
Benefits
• Oral agents: QD dosing
• A1c reduction ~ 1%
• PPBG > FBG control
•
•
•
•
Low risk of hypoglycemia
Well tolerated
Weight neutral
Clinical benefits:
• CKD/ESRD
• Elderly
• Additional benefits?
Concerns
• FDA Warnings: Severe
arthralgia, pancreatitis
• Upper respiratory infections
• Hypersensitivity reactions
• Additional Concerns
• Cardiovascular effects?
What is the role of Sodium
Glucose CoTransporter-2?
MOA of SGLT-2 Inhibitors
http://www.diabetesendocrinology.in/diabetes/type-2-diabetes-new-oral-tablet-sglt2-inhibitor/
SGLT-2 INHIBITORS
INVOKANA (CANAGLIFLOZIN)
FARXIGA
(DAPAGLIFLOZIN)
JARDIANCE (EMPAGLIFLOZIN)
Benefits of
SGLT- Inhibitors
Weight loss
Low risk of
hypoglycemia
Novel MOA
Once daily
ORAL
Adverse Effects
Urinary Tract
Infection
Yeast infection
Dehydration
Electrolyte
changes
Pharmacology
INVOKANA
FARXIGA
JARDIANCE
(CANAGLIFLOZIN)
(DAPAGLIFLOZIN)
(EMPAGLIFLOZIN)
100 & 300 mg
5 & 10 mg
10 & 25 mg
10.6 – 13.1
~ 12.9
~ 12.4
Metabolism
UGT1A9, UGT2BA
UGT1A9
UGT2B7, UGT1A3
UGT1A8, UGT1A9
Elimination
Fecal / Renal
Renal / Fecal
Renal / Fecal
Renal Dosing (eGFR):
Not Recommended
< 45 mL/min
< 60 mL/min
< 45 mL/min
Dosing Frequency
Dosage
Half-life (hours)
Additional Precautions
KETOACIDOSIS
• USA: 20 Cases (03/2013 – 06/2014)
• 101 Cases worldwide; T2DM
• Euglycemic diabetic ketoacidosis
• Be vigilant
•
•
•
Check ketone levels
Stop SGLT2 Inhibitors 3 days prior to surgery
Caution in T1DM, off-label
BLADDER CANCER
• Dapagliflozin
BONE FRACTURES
• Canagliflozin
• Class effect?
Macrovascular Benefits…
↓ Composite endpoint:
CV death,
nonfatal MI
& nonfatal stroke
Case: Part IV
A few years later, HP is diagnosed with CKD and her
CrCl = 50 mL/min. Which of the following agents should
NOT be used with her current CKD status?
a.
b.
c.
d.
Trulicity (Dulaglutide)
Tradjenta (Linagliptin)
Invokana (Canagliflozin)
Farxiga (Dapagliflozin)
SGLT-2 Inhibitors: Clinical Pearls
Benefits
• Novel MOA: Oral QD dosing
• A1c reduction ~ 1%
• FBG > PPBG control
•
•
•
•
Weight loss
Low risk of hypoglycemia
CV mortality
Additional benefits?
Concerns
• FDA Warnings:
• Euglycemic ketoacidosis
• Bone fractures (Canagliflozin)
•
•
•
•
UTIs & genital mycotic infections
Do NOT use in CKD/ESRD
Caution in elderly
Caution interpreting
macrovascular outcomes
• Additional Concerns?
SUMMARY
Place in Therapy: ADA Position Statement
Inzucchi et al.
Comparison of the 3 Classes
GLP1- RAs
DPP-4 Inhibitors
SGLT2 Inhibitors
BID, QD , QWeek
QD
QD
Subcutaneous
Oral
Oral
Weight Effects
LOSS
NEUTRAL
LOSS
Hypoglycemia Risk
LOW
LOW
LOW


x
Administration
Route
CKD Use
(Albiglutide & Dulaglutide)
Adverse Effects
N/V/D
Injection Site Reactions
URI
Nasal pharyngitis
UTI
Yeast Infections
FDA Warnings
Pancreatitis
Thyroid C-Cell Tumors
Kidney Failure
Pancreatitis
Severe Arthralgia
DKA
Bone Fractures
Greatest A1c
(long-acting)
Compliance (long-acting)
Reduced insulin dose
Modest A1c
CKD
Elderly
Well Tolerated
Modest A1c
Novel MOA
CV Benefits
Caution in elderly
Use in T1DM?
Therapeutic Use
Highlights
THANK YOU!