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 ?