Jardiance - Dr Sam`s Rotation

Report
JARDIANCE:
Newly Approved Drug to Lower HbA1C in
Type-2 diabetes
Presented By:
Rahul Patel, MS, PharmD. Candidate 2015
Dr. Sam Shimomura, Associate Dean,
Western University of Health Sciences
Date:09/25/2014
Disclosure
I, Rahul Patel, have no conflict of interest to
disclose.
Objectives
Pharmacists will be able to:
• Describe SGLT2 inhibitors
• Compare available SGLT-2 inhibitors
• Identify ideal candidates for SGLT2 inhibitors
1
Introduction
• Diabetes mellitus is a chronic disease often requiring
complex treatment regimens to prevent long-term
complications.
• According to the 2012 statistics from CDC, 29.1 million
people have diabetes.
• The total direct and indirect estimated cost of the disease
in 2014 is 245 billion.
Introduction (Cont’d)
Type 2 diabetes is characterized by 3 factors
• Persistent hyperglycemia
• Impaired β-cell function
• Insulin resistance
SGLT2 Inhibitors: A Novel Class
Sodium-Glucose Co-transporter 2
(SGLT-2) inhibition works directly on
glucose, independent of β-cell function
and insulin
• 90% of the glucose is reabsorbed by
SGLT2 , remaining 10% by SGLT1
2
Currently Approved SGLT2
Inhibitors
Invokana (canagliflozin)
Mfg by: Janssen Pharmaceuticals, Inc.
Licensed from Mitsubishi Tanabe Pharma Corporation
Approved in Mar’2013
Farxiga (dapagliflozin)
Mfg By: Bristol-Myers Squib Company
Mkt By: AstraZeneca Pharmaceuticals LP
Approved in Jan’2014
Jardiance (empagliflozin)
Mfg By: Eli Lilly and Company
Approved in Aug’2014
3
Jardiance Efficacy as Monotherapy
Results at Week 24 From a Placebo-Controlled Monotherapy Study of JARDIANCE
Efficacy in Combination
3
Results at Week 24 From a Placebo-Controlled Study for JARDIANCE used in
Combination with Metformin
3
Efficacy in Combination
Results at Week 24 From a Placebo-Controlled Study for JARDIANCE in Combination
with Metformin and Sulfonylurea
3
Adverse Effects of Jardiance
Adverse Reactions Reported in ≥2% of Patients Treated with JARDIANCE and
Greater than Placebo in Pooled Placebo-Controlled Clinical Studies of
JARDIANCE Monotherapy or Combination Therapy
Hypoglycemia
3
Jardiance vs Farxiga
Jardiance
Farxiga
Indication


Usual Dose



Dosing In Renal
Impairment
As an adjunct to diet and exercise to
improve glycemic control in adults with
T2DM
Starting dose: 10 mg by mouth daily
Maximum dose: 25 mg once daily
GFR ≤ 45 ml/min/1.73m2, end-stage renal
disease, or dialysis: contraindicated




Dosing In Hepatic
Impairment

No dosage adjustment necessary

Drug Interactions


Administration

Insulin or Insulin Secretagogues: increases
risk of hypoglycemia
Take in the morning, with or without food
Metabolism

Primarily metabolized by UGT2B7, UTG1A3,
UGT1A8, and UGT1A9



As an adjunct to diet and exercise to
improve glycemic control in adults
with T2DM
Starting dose: 5 mg by mouth daily
Maximum dose: 10 mg once daily
GFR 30 to 60 ml/min/1.73m2: not
recommended
GFR ≤ 30 ml/min/1.73m2, end-stage
renal disease, or dialysis:
contraindicated
Use is not recommended in severe
hepatic impairment (has not been
studied)
No significant drug interactions
Take in the morning, with or without
food
Primarily metabolized by UGT1A9 to
an inactive metabolite
Weak substrate of P-glycoprotein
4
Jardiance vs Farxiga
Pharmacokinetics
Most common
Adverse
Reactions
(Frequency)
Price
Jardiance
Farxiga

Onset of action: within 24 hours

Onset of action: within 24 hours

Protein binding: 86.2%; not affected by
renal or hepatic impairment

Protein binding: 91%; not affected by renal
or hepatic impairment

Oral bioavailability: 79%

Oral bioavailability: 78%

Half-life elimination: 12.4 hours

Half-life elimination: 12.9 hours

Excretion: urine (54.4%; half as
unchanged drug); feces (41.2%,
primarily unchanged drug)
Female genital infection (6.4% - 5.4%)
Urinary tract infection (7.6% - 9.3%)
Upper respiratory tract infections (4.0%
- 3.1%)
Increased urination (3.4% - 3.2%)
10 mg or 25 mg (30): $361.06

Excretion: urine (75%; <2% as unchanged
drug); feces (21%, 15% as unchanged drug)


Female genital infection (6.9% - 8.4%)
Urinary tract infection (4.3% - 5.7%)

5 mg or 10 mg (30): $347.04





UGT enzyme inducers include rifampin, phenytoin, phenobarbital, and ritonavir.
UGT = uridine glucuronyl transferase
Which SGLT-2 inhibitor to use ?
Efficacy comparison* as monotherapy compared to placebo in 24 weeks trial
Jardiance
Farxiga
Invokana5
(10mg,25mg)
(5mg,10mg)
(100mg,300mg)
0.7-0.9
0.5-0.7
0.91-1.16
FPG reduction
(mg/dL)
31-36
19.9-24.7
36-43
Weight Loss (in
Kg)
2.5-2.8
2.8-3.2
2.2-3.3
SBP reduction
(mmHg)
2.6-3.4
2.3-3.6
3.7-5.4
HbA1C reduction
(%)
*Note: comparison in individual trials and not in head to head clinical trials
Which SGLT-2 inhibitor to use ?
Farxiga :
• Carries a warning of Bladder cancer risk.
• Newly diagnosed Bladder cancer has been reported in 0.17% of subjects
• Use not recommended in Hepatic Impairment (not studied )
Jardiance:
• Can be used in Hepatic Impairment
Invokana:
• Use not recommended in Hepatic Impairment( not studied)
• Dose related Hyperkalemia
• >5.4mEq/mL(12%-27%), ≥6.5mEq/mL (2%)
Effects of SGLT-2 inhibitors
Benefits:
•
•
•
•
•
•
HbA1C decrease 0.5-1%
Weight Loss
No edema
Once a day dosing
A little decrease of SBP
Minimal Hypoglycemia
Drawbacks:
• UTI, balanitis, mycotic vulvovaginal infection
• Mild transient decrease in eGFR
• Not studied in Type 1 diabetes
Current Place in Therapy
• FDA approved as adjunct to diet and exercise to control blood
glucose.
• Also studied in combination with metformin, SU, insulin,
pioglitazone
• Can be used as second line, after metformin ( because
metformin is more studied and approved as first line),
however, its cost should be considered.
Conclusion
• Since the mechanism of action is independent of the insulin and β-cell
function, theoretically it can be used as long as renal function is okay.
• It is a new drug ,therefore should be used with extra monitoring, renal
function especially.
• Long term effects unknown
• No studies have been done to see that if the decrease in HbA1C correlates
with the decrease in macro and micro vascular complications associated
with diabetes.
Ideal patient
Which of the following is a candidate for
therapy with Jardiance ?
a.
A 25 year old pregnant woman with Type 2 diabetes.
b.
A 38 year old male, obese patient with Type 2 diabetes having
normal kidney function
c.
A 68 year old male patient with Type 2 diabetes.
d.
A 25 year old male patient with Type 1 diabetes
References
1. http://care.diabetesjournals.org/content/early/2013/03/05/dc12-
2625.full.pdf+html
2. Ele Ferrannini & Anna Solini, SGLT2 inhibition in diabetes
mellitus: rationale and clinical prospects, Nature Reviews
Endocrinology 8, 495-502 (August 2012)
3. Jardiance package insert
4. Farxiga package insert
5. Invoka package insert
Questions ?

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