Updates in Diabetes Mellitus · PDF fileUpdates in Diabetes Mellitus Pharmacotherapy Jennifer...

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.

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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)

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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

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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

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A1c

Kg

SBP

Glu

SGLT2 Adverse Effects

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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

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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

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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

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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).

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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

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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

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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

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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)

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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.

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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

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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)

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-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

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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 $$$

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Pros Cons

Weight neutral Low risk of hypoglycemia

Moderate efficacy Costly

Rapid-Acting Inhaled Insulin

Afrezza® (technosphere insulin)

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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

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-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

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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

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Anticipate arrival to United States market in 1st quarter of 2015

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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

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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

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