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 Post test questions should reflect 2 objectives,( symptoms, ideal candidate, pregnancy)

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.

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

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

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.

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

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

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

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

Hypoglycemia3

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

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

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 (%) 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 *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

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.

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. 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.

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 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

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 ?