1. 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

2. Disclosure
I, Rahul Patel, have no conflict of interest to disclose.

3. Objectives Pharmacists will be able to: Describe SGLT2 inhibitors
Compare available SGLT-2 inhibitors
Identify ideal candidates for SGLT2 inhibitors
Post test questions should reflect 2 objectives,( symptoms, ideal candidate, pregnancy)

4. Introduction1
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.

5. Introduction (Cont’d)
Type 2 diabetes is characterized by 3 factors
Persistent hyperglycemia
Impaired β-cell function
Insulin resistance

6. SGLT2 Inhibitors: A Novel Class2
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

7. 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
The FDA is requiring five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the PREA.

8. Jardiance Efficacy as Monotherapy3
Results at Week 24 From a Placebo-Controlled Monotherapy Study of JARDIANCE

9. Efficacy in Combination3
Results at Week 24 From a Placebo-Controlled Study for JARDIANCE used in
Combination with Metformin
Make table

10. Efficacy in Combination3
Results at Week 24 From a Placebo-Controlled Study for JARDIANCE in Combination
with Metformin and Sulfonylurea

11. Adverse Effects of Jardiance3
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

12. Hypoglycemia3

13. Jardiance vs Farxiga Jardiance Farxiga Indication
As an adjunct to diet and exercise to improve glycemic control in adults with T2DM
Usual Dose
Starting dose: 10 mg by mouth daily
Maximum dose: 25 mg once daily
Starting dose: 5 mg by mouth daily
Maximum dose: 10 mg once daily
Dosing In Renal Impairment
GFR ≤ 45 ml/min/1.73m2, end-stage renal disease, or dialysis: contraindicated
GFR 30 to 60 ml/min/1.73m2: not recommended
GFR ≤ 30 ml/min/1.73m2, end-stage renal disease, or dialysis: contraindicated
Dosing In Hepatic Impairment
No dosage adjustment necessary
Use is not recommended in severe hepatic impairment (has not been studied)
Drug Interactions
Insulin or Insulin Secretagogues: increases risk of hypoglycemia
No significant drug interactions
Administration
Take in the morning, with or without food
Metabolism
Primarily metabolized by UGT2B7, UTG1A3, UGT1A8, and UGT1A9
Primarily metabolized by UGT1A9 to an inactive metabolite
Weak substrate of P-glycoprotein

14. Jardiance vs Farxiga4 Jardiance Farxiga Pharmacokinetics
Onset of action: within 24 hours
Protein binding: 86.2%; not affected by renal or hepatic impairment
Oral bioavailability: 79%
Half-life elimination: 12.4 hours
Excretion: urine (54.4%; half as unchanged drug); feces (41.2%, primarily unchanged drug)
Protein binding: 91%; not affected by renal or hepatic impairment
Oral bioavailability: 78%
Half-life elimination: 12.9 hours
Excretion: urine (75%; <2% as unchanged drug); feces (21%, 15% as unchanged drug)
Most common Adverse Reactions (Frequency)
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%)
Female genital infection (6.9% - 8.4%)
Urinary tract infection (4.3% - 5.7%)
Price
10 mg or 25 mg (30): $361.06
5 mg or 10 mg (30): $347.04
UGT enzyme inducers include rifampin, phenytoin, phenobarbital, and ritonavir.
UGT = uridine glucuronyl transferase

15. Which SGLT-2 inhibitor to use ?
Efficacy comparison* as monotherapy compared to placebo in 24 weeks trial
Jardiance
(10mg,25mg)
Farxiga
(5mg,10mg)
Invokana5
(100mg,300mg)
HbA1C reduction (%)
FPG reduction (mg/dL)
31-36
36-43
Weight Loss (in Kg)
SBP reduction (mmHg)
*Note: comparison in individual trials and not in head to head clinical trials
*Note: comparison in individual trials and not in head to head clinical trials

16. 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%)
The FDA is requiring five postmarketing studies for Invokana: a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; a bone safety study; and two pediatric studies under the PREA.

17. 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

18. 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.
It may be debatable as a second line or first line therapy, because metformin has greater HBA1c control, its weight neutral and cheap and have more data. But as third line therapy it is probably best suited if the patient is a candidate. But having said that, ultimately it’s physician’s and patients’ choice.

19. 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.

20. Ideal patient
Which of the following is a candidate for therapy with Jardiance ?
A 25 year old pregnant woman with Type 2 diabetes.
A 38 year old male, obese patient with Type 2 diabetes having normal kidney function
A 68 year old male patient with Type 2 diabetes.
A 25 year old male patient with Type 1 diabetes

21. References 1.
2. Ele Ferrannini & Anna Solini, SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects, Nature Reviews Endocrinology 8, (August 2012)
3. Jardiance package insert
4. Farxiga package insert
5. Invoka package insert

22. Questions ?