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

Introduction

1 • 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

2 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

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

Jardiance Efficacy as Monotherapy

3

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

Efficacy in Combination

3

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

Adverse Effects of Jardiance

3

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

Indication Usual Dose Dosing In Renal Impairment Dosing In Hepatic Impairment Drug Interactions Administration Metabolism

 

Jardiance

 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/1.73m

2

,

end-stage renal disease, or dialysis: contraindicated No dosage adjustment necessary Insulin or Insulin Secretagogues: increases risk of hypoglycemia Take in the morning, with or without food Primarily metabolized by UGT2B7, UTG1A3, UGT1A8, and UGT1A9     

Farxiga

 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/1.73m

2 : not recommended GFR ≤ 30 ml/min/1.73m

2 , 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

Jardiance vs Farxiga

4

Pharmacokinetics Jardiance

 Onset of action: within 24 hours   Protein binding: 86.2%; not affected by renal or hepatic impairment Oral bioavailability: 79%

Farxiga

 Onset of action: within 24 hours  Protein binding: 91%; not affected by renal or hepatic impairment  Oral bioavailability: 78%  Half-life elimination: 12.4 hours  Half-life elimination: 12.9 hours

Most common Adverse Reactions (Frequency) Price

      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

HbA1C reduction (%) FPG reduction (mg/dL) Weight Loss (in Kg) SBP reduction (mmHg) Jardiance

(10mg,25mg) 0.7-0.9

31-36 2.5-2.8

2.6-3.4

Farxiga

(5mg,10mg) 0.5-0.7

19.9-24.7

2.8-3.2

2.3-3.6

Invokana 5

(100mg,300mg) 0.91-1.16

36-43 2.2-3.3

3.7-5.4

* 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.

c.

d.

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

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 ?