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Updates in Diabetes Mellitus Pharmacotherapy
Jennifer Grelle, Pharm.D., BCPS
Clinical Pharmacist, Abilene Regional Medical Center
Assistant Professor, Adult Medicine Division
Disclosures
• None
2
Learning Objectives
• Review the newly approved anti-glycemic agents.
• Discuss the impact of new agents on current treatment recommendations.
• Design a regimen using the new medications when given a patient case.
3
4
2013 2014
Recent FDA Drug Approvals
Jardiance® (empagliflozin)
Afrezza® (insulin human)
Tanzeum® (albiglutide)
Bydureon® (exenatide ER)
Farxiga® (dapagliflozin)
Trulicity® (dulaglutide)
Jan Mar Feb Apr May Jun Jul Aug Sep Oct
Invokana® (canagliflozin)
Nesina® (alogliptin)
Jan Mar Feb Apr May Jun Jul Aug Sep Oct Nov Dec
2013
2014
New Drugs by Pharmacologic Class
• Sodium-glucose co-transporter 2 (SGLT2) Inhibitors • Invokana® (canagliflozin)
• Farxiga® (dapagliflozin)
• Jardiance® (empagliflozin)
• Glucagon-Like Peptide 1 Agonist • Bydureon® (exenatide extended-release)
• Tanzeum® (albiglutide)
• Trulicity® (dulaglutide)
• Dipeptidyl peptidase-4 inhibitor • Nesina® (alogliptin)
• Rapid Acting Inhaled Insulin • Afrezza® (technosphere insulin)
5
Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors
Invokana® (canagliflozin)
Farxiga® (dapagliflozin)
Jardiance® (empagliflozin)
SGLT2 Inhibitor Mechanism of Action
7
Image from: http://www.diabetologists-abcd.org.uk/n3/Dapagliflozin.pdf
SGLT2-Inhibitor
Glucose
SGLT2
Proximal tubule
Glucose Filtration
SGLT2 Inhibitors: How do they work? 8
Plasma glucose (mg/dL)
200 300
Glu
cose
fi
ltra
tio
n/r
eab
sorp
tio
n/e
xcre
tio
n
(mg
/min
)
Diabetic Threshold
100
200
300
400 SGLT2 Inhibition
SGLT2 Inhibition
Normal Threshold
Diabetic glucose transport rate
Normal glucose transport rate
Jung CH, et al. Diabetes Metab J. 2014;38(4):261-273.
SGLT2 Inhibitor Dosing
9
Initial Maximum
Invokana® (canagliflozin)
100 mg PO daily prior to 1st meal of day
300 mg PO daily
Farxiga® (dapagliflozin)
5 mg PO daily with/without food
10 mg PO daily
Jardiance® (empagliflozin)
10 mg PO daily with/without food
25 mg PO daily
SGLT2 Inhibitor Renal Adjustments
10
< 60 mL/min/1.73 m2 < 45 mL/min/1.73 m2
Invokana® (canagliflozin)
100 mg PO daily* Screen for UGT enzyme
inducer meds – do not use
Farxiga® (dapagliflozin)
Jardiance® (empagliflozin)
No adjustment
Canagliflozin: HgA1c Changes 11
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
% C
han
ge in
A1
c in
26
or
52
* w
ks
Comparator CANA 100 mg CANA 300 mg
PLACEBO GLIM* SITA 100 mg* MET-SU* MET-PIO
Add-On
Diabetes Obes Metab. 2014;16:467-477. Int J Clin Pract. 2013;67(12):1267-1282.
Diabetes Care.2013;36(9):2508-2515. Lancet. 2013;382(9896):941-950. Diabetes Obes Metab. 2013;15(4):372-382.
Canagliflozin: Weight Changes 12
-5
-4
-3
-2
-1
0
1
2
We
igh
t C
han
ge f
rom
Bas
elin
e (
kg)
Comparator CANA 100 mg CANA 300 mg
PLACEBO GLIM* SITA 100 mg* MET-SU* MET-PIO
Add-On
Diabetes Obes Metab. 2014;16:467-477. Int J Clin Pract. 2013;67(12):1267-1282.
Diabetes Care.2013;36:2508-2515. Lancet. 2013;382(9896):941-950. Diabetes Obes Metab. 2013;15(4):372-382.
PLACEBO GLIM* SITA 100 mg* MET-SU* MET-PIO
SGLT-2 Inhibitor Class Efficacy/Safety Data
Reduction up to 1% with monotherapy Reduction of 0.6-0.8% as “add-on” therapy
Average of 3 kg weight loss
Diuretic effect results in ~5 mmHg decrease
Hypoglycemia not anticipated based on MOA
13
A1c
Kg
SBP
Glu
SGLT2 Adverse Effects
14
Genital mycotic & urinary tract infections
• Females > males
Orthostatic hypotension & postural dizziness
• Infrequent but greater risk with older age, concomitant loop
diuretics, and decreased renal function
Lipid Parameters
• LDL, HDL, TGs (wash?)
Malignancies
• Dapagliflozin was associated with an increased number of breast and bladder cancers.
SGLT2 Inhibitors Summary
• Place in therapy: Add-on therapy or intolerant to metformin
• Counseling Points
• Monitor for signs/symptoms of yeast infections & UTIs
• Changes in usual urination patterns (volume, frequency)
• Dehydration
15
Pros Cons
High efficacy Weight loss Very low risk of hypoglycemia
Costly Reduced efficacy w/CKD May result in hypotension
Glucagon-Like Peptide 1 Agonist
Bydureon® (exenatide extended-release)
Tanzeum® (albiglutide)
Trulicity® (dulaglutide)
GLP-1 Agonist Mechanism of Action 17
Image from: http://stomachpicture.com/wp-content/uploads/2014/07/picture-of-abdominal-organs-114.jpg
glucose-dependent insulin secretion
inappropriate glucagon secretion
satiety
gastric emptying
GLP-1 Agonists Dosing
18
Agent Dosing
Byetta® (exenatide) 5-10 mcg SubQ BID
Bydureon® (exenatide ER) 2 mg SubQ weekly
Tanzeum® (albiglutide) 30-50 mg SubQ weekly
Trulicity® (dulaglutide) 0.75-1.5 mg SubQ weekly
Victoza® (liraglutide) 0.6-1.2 mg SubQ daily
Exenatide Efficacy: ER vs. IR
-1.9
-1.6 -1.5
-0.9
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Me
an A
1c
Ch
ange
(%
)
Exenatide ER
Exenatide BID
19
DURATION 1 (30 weeks)
DURATION 5 (24 weeks)
p=0.002 p<0.0001
At 30 weeks, no difference in weight loss between ER and IR (-3.7 vs. -3.6 kg).
19
Buse JB. Diabetes Care. 2010;33(6):1255-1261. Blevins T. J Clin Endocrinol Metab. 2011;96(5):1301-1310.
Exenatide ER Efficacy
-1.5 -1.5 -1.6
-1.2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Me
an A
1c
Ch
ange
(%
)
Exenatide ER MET PIO SITA
20
DURATION 4 (26 weeks)
p<0.001 -1.3
-1.5
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Exenatide ER Liraglutide
DURATION 6 (26 weeks)
95% CI 0.08-0.33 Non-Inferiority CI Margin < 0.25%
LIRA resulted in 0.9 kg > weight loss (p=0.0005).
Mann KV, et al. Diabetes Metab Syndr Obes. 2014;7:229-239.
Tanzeum® (albiglutide) Efficacy
-0.7
-0.9
0.2
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
Me
an A
1c
Ch
ange
(%
)
ALBI 30 mg ALBI 50 mg Placebo
-0.78
-0.99
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
ALBI 50 mg LIRA 1.8 mg
HARMONY 2 (52 weeks)
HARMONY 7 (32 weeks)
Non-Inferiority p value = 0.08
p<0.0001
21
LIRA resulted in 1.55 kg > weight loss (p<0.05).
Trujillo JM, et al. Ann Pharmacother. 2014 Aug 18 [ahead of print]
Trulicity® (dulaglutide) Efficacy
-1.42 -1.36
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
DULA 1.5 mg LIRA 1.8 mg
AWARD 6 26 weeks
Non-Inferiority p value < 0.0001
-1.07
-1.36
-0.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Me
an A
1c
Ch
ange
(%
)
DULA 0.75 mgDULA 1.5 mgExenatide IR
*
*
AWARD 1 52 weeks
*Superiority p value < 0.001
22
LIRA resulted in 0.71 kg > weight loss (p=0.011).
Wysham C, et al. Diabetes Care. 2014;37(8):2159-2167. Dungan KM, et al. Lancet. 2014 Jul 10 [ahead of print]
GLP-1 Agonist Adverse Effects
• Gastrointestinal (Most common) • Nausea, vomiting and/or diarrhea
• Dose dependent and usually resolves after 8 weeks of therapy
• Exenatide IR > liraglutide ~ dulaglutide ~exenatide ER > albiglutide
• Pancreatitis (Rare) • If suspect pancreatitis, discontinue therapy.
• If pancreatitis confirmed and unknown etiology, do not resume therapy.
• Thyroid Tumors (all agents w/labeling except Byetta®) • Contraindicated in patients with history or family history of:
• Medullary thyroid carcinoma (MTC)
• Multiple endocrine neoplasia syndrome Type 2 (MEN2)
23
GLP-1 Agonist Summary
• Place in therapy: Add-on
• Clinical Pearls
• Concurrent use of sulfonylurea and/or insulin increases risk for hypoglycemia.
• If dose missed, administer within 3 days of regularly scheduled time.
• May administer each of the new GLP-1 agonists without regard for meals.
• Byetta® Bydureon®: may observe increased glucose levels for ~ 2 weeks.
24
Pros Cons
High efficacy Weight loss Low risk of hypoglycemia
GI side effects Injectable Costly
Dipeptidyl peptidase-4 inhibitors
Nesina® (alogliptin)
Tradjenta® (linagliptin)
Onglyza® (saxagliptin)
Januvia® (sitagliptin)
Dipeptidyl Peptidase IV Inhibitors Mechanism of Action
26
GLP-1 “Active”
DPP-4 Enzyme
DPP-4 Inhibitors
GLP-1 “In-Active”
GLP-1 “Active”
Nesina® (alogliptin)
• FDA approved for Type 2 DM
• Recommended Dose • 25 mg PO daily
• Renal Impairment • CrCl > 30 to < 60 mL/minute: 12.5 mg PO daily
• CrCl > 15 to < 30 mL/minute: 6.25 mg PO daily
• CrCl < 15 mL/minute or hemodialysis: 6.25 mg PO daily
• Peritoneal dialysis: Not studied
• Hepatic Impairment • Mild-Moderate (Child-Pugh A & B): no adjustment needed
• Severe (Child-Pugh C): avoid use (not studied)
27
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
% C
han
ge in
A1
c in
26
wks
ALOG 12.5 mg ALOG 25 mg Comparator
Nesina® (alogliptin) Efficacy 28
PLACEBO
PIO PIO MET-PIO Insulin
Add-On
28
Nesina® (alogliptin) Safety
• Hypoglycemia
• Rates of 1.5-3% observed in clinical studies
• Common Adverse Effects
• Headache (4-5%)
• Upper respiratory tract infection (4%)
• Serious Adverse Effects
• Fatal & non-fatal liver failure (draw liver enzymes at baseline)
• Pancreatitis
• Steven-Johnson Syndrome
• Angioedema
29
Nesina® (alogliptin) Summary
• Place in Therapy: Add-On
• Combination Agents
• Kazano® (alogliptin + metformin)
• Oseni® (alogliptin + pioglitazone)
• Comparison to other DPP-4 inhibitors
• Similar efficacy, hypoglycemia rates and $$$
30
Pros Cons
Weight neutral Low risk of hypoglycemia
Moderate efficacy Costly
Rapid-Acting Inhaled Insulin
Afrezza® (technosphere insulin)
32
Afrezza® Dosing
33
Image from: http://www.rxlist.com/afrezza-drug/indications-dosage.htm
Afrezza® (technosphere) Efficacy Data
-0.2
-0.41
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
% A
1c
Re
du
ctio
n
TI + Lantus Aspart + Lantus
34
-0.58
-0.7
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
TI + Lantus Premix 70/30
T1DM T2DM
Neumiller JJ, et al. Ann Pharmacother. 2010;44:1231-1239. Santos C, et al. Clin Ther. 2014;36(8):1275-1289.
Afrezza® Therapy Considerations
• Contraindications
• Asthma
• Chronic obstructive pulmonary disease
• Warning
• Smokers
• Lung cancer
• Monitoring
• Assess pulmonary function tests: baseline, at 6 months, and annually
35
Afrezza® (rapid-acting inhaled insulin)
• Place in Therapy (approval in adults only):
• Uncontrolled T2DM after adequate oral therapy trial
• Use in T1DM management in place of injectable rapid/intermediate-acting insulin
36
Anticipate arrival to United States market in 1st quarter of 2015
37
Putting the pieces together: Therapy Selection
Monotherapy Metformin
1st Add-On Therapy
Sulfonylurea (SU)
Thiazolidine-dione (TZD)
DPP-4 Inhibitor (DPP-4i)
GLP-1 Agonist (GLP-1-RA)
Basal insulin
2nd Add-On Therapy
PLUS 1 of the following:
TZD DPP-4i
GLP-1-RA SGLT2-i
Basal Insulin
SU DPP-4i
GLP-1-RA SGLT2-i
Basal Insulin
SU TZD
SGLT2-i Basal Insulin
TZD DPP-4i
GLP-1-RA SGLT2-i
Multi-Dose Insulin
Basal-bolus insulin
Efficacy (HgA1c) Insulin > MET-TZD-SU-GLP-1-RA > DPP-4i
Weight Loss GLP-1-RA > MET > DPP-4 > SU-TZD-Insulin (gain)
Hypoglycemia Insulin > SU > MET-TZD-GLP-1-RA-DPP-4i
T2DM Treatment Strategies
SGLT2-i
Patient Case
A 52 year-old female with T2DM presents to your clinic. She is currently receiving metformin 1000 mg PO BID and her HbA1c today is 8.5%.
PMH: HTN, COPD, thyroid carcinoma, chronic pancreatitis
Vitals: BP 138/89 HR 75 eGFR: 95 mL/min/m2
39
Which of the following would be the most appropriate add-on therapy?
a. Invokana® 100 mg PO daily b. Tanzeum® 30 mg SubQ weekly c. Nesina® 6.25 mg PO daily d. Afrezza® 5 units AC + Lantus 10 units QPM
QUESTIONS Jennifer.grelle@ttuhsc.edu
40
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