Sodium-glucose co-transporter 2 (SGLT2) inhibitors and their place in therapy Katee Lira, PharmD PGY2 Ambulatory Care Pharmacy Resident St. Vincent Joshua Max Simon Primary Care Center September 18, 2014 This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation.

Objectives Recall the mechanism of action of SGLT2 inhibitors List potential benefits and concerns of SGLT2 inhibitors Recognize available SGLT2 inhibitors and appropriate dosing Identify place in therapy for SGLT2 inhibitors

Components that Affect Hyperglycemia Which of these components do you think SGLT-2 Inhibitors affect? Response: increased glucose reabsorption Catch line from drug rep: You can eat your cake and pee it too?  I don’t like this because this may give patients the impression that they don’t have to watch their diet. DeFronzo RA. Diabetes. 2009;58:773-795.

How Do SGLT2 Inhibitors Work? Glucose in blood NORMALLY ALL FILTERED GLUCOSE IS REABSORBED Highly specific for the kidney and SGLT2 transporter It works by blocking the reabsorption of glucose (blood sugar) by the kidney, increasing glucose excretion, and lowering blood glucose levels in diabetics who have elevated blood glucose levels Effectiveness is independent of insulin -- This mechanism of action is independent of insulin so this could be a benefit for someone who is having insulin resistance. Bailey CJ, Day C. SGLT2 inhibitors: glucuretic treatment for type 2 diabetes. BR J Diabetes Vasc Dis. 2010; 10:193-199. Glucosuria Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559.

What % A1c Reduction will SGLT2 Inhibitors Have? 0.5% 1% 1.5% 2% DPP4 inhibitors SGLT2 inhibitors TZDs Metformin Sulfonylureas Diabetes Care 2014;37: S14-79.

Highlights of SGLT2 Inhibitors Indication: adults with type 2 diabetes (T2DM) Not approved for <18 years old, T1DM, or DKA Ongoing studies Pediatrics CV outcomes Benefits Weight reduction: ~2-3kg Systolic blood pressure lowering: ~3-5mmHg Low risk of hypoglycemia Systolic blood pressure lowering due to osmotic diuresis A1c lowering: ~1% (many different results ranging 0.7-1.1%) 75g urine glucose = 300kcal/day Weight loss observed with monotherapy and as add-on combination therapy Low risk of hypoglycemia by itself. May have hypoglycemia in combination with medications that cause hypoglycemia Post marketing studies include: CV outcomes trial, pharmacovigilance program to monitor for serious side effects, a bone safety study, two pediatric studies Thoretically, may be used for kids and Type1 diabetics in the future List JF, et al. Diabetes Care. 2009;32:650-657. (for weight reduction) Stenlof K, et al. Diabetes Obes Metab. Published online January 24, 2013. (BP and A1c reduction) List JF, et al. Diabetes Care. 2009;32:650-657. Stenlof K, et al. Diabetes Obes Metab. Published online January 24, 2013. Invokana® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2013. Farxiga™ [package insert. Wilmington, DE: AstraZeneca. 2014.

FDA Approved SGLT2 Inhibitors Agent Canagliflozin INVOKANA® Dapagliflozin FARXIGA™ Empagliflozin JARDIANCE® Dosing Initial: 100mg daily Max: 300mg daily Initial: 5mg daily Max: 10mg daily Initial: 10mg daily Max: 25mg daily Administration Before the first meal of the day In the morning with or without food Renal Dose Adjustments Yes Cost ~$350 for 30 tablets TBD Patient Assistance Available Talking points: -When you increase dose therapies -Other agents: agent being studied with renal impairment Currently not available but being studied: Ipragliflozin and Empagliflozin Prior to initiation: assess renal function  Discontinue canagliflozin if GFR is consistently below 45mL/min  Discontinue dapagliflozin if GFR is consistently below 60mL/min Both are Pregnancy Category C  No well controlled studies have been conducted in pregnant women is not indicated for patients with type 1 diabetes, diabetic ketoacidosis, severe renal impairment, or end-stage renal disease or for patients receiving dialysis. It is the third oral SGLT2 inhibitor to receive FDA approval. Urinary tract infections and female genital infections were the most common adverse effects observed in the clinical trials. must conduct 4 postmarketing studies, including the completion of a cardiovascular outcomes study now underway, and 3 others delving into pediatric issues.  d/c if crcl<45. dose 10mg starting and max 25mg once daily in the morning Cost: Wholesale price of $8.77/tablet --FYI— Dapagliflozin Renal dosing GFR <60mL/min – not recommended GFR <30mL/min –contraindicated Canagliflozin Renal dosing GFR 45 – <60mL/min – 100mg daily GFR 30 – 45mL/min – not recommended GFR<30mL/min – contraindicated Invokana Patient assistance: 12 months at no cost if private insurance Maximum savings of $3900 annually Farxiga Patient assistance: Maximum savings of $346 per 30‑day supply Invokana® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2013. Farxiga™ [package insert]. Wilmington, DE: AstraZeneca. 2014. Jardiance® [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. 2014.

Warnings for SGLT2 Inhibitors Adverse drug reactions Precautions Increased urination Vaginal yeast infections Urinary tract infections Nasopharyngitis (dapagliflozin) Hypotension Impairment in renal function Hyperkalemia Hypoglycemia Hypersensitivity Increase in LDL Bladder cancer (dapagliflozin) hypoglycemia (in combination with insulin or insulin secreatgogues) Talk about monitoring for patient and physicians Hypotension- assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure or on diuretics, ACE inhibitors, or ARBs Impairment in renal function- increase serum creatinine and decreases GRF Hyperkalemia- monitor potassium levels in patients with impaired renal function or those predisposed to hyperkalemia Genital mycotic infections can cause dehydration, leading to a drop in blood pressure (hypotension) that can result in dizziness and/or fainting and a decline in renal function. The elderly, patients with impaired renal function, and patients on diuretics to treat other conditions appeared to be more susceptible to this risk Malignancies: bladder and breast, not significantly different % UTI 4%, 4.6%, 12.5%, and 5.7% for placebo, DAPA 2.5mg, 5mg, and 10mg groups; 8%, 4%, 7%, and 8%; 6.2%, 3.9%, 6.9%, and 5.3%; 8.4% DAPA vs 4.1% placebo % genital infections 1.3%, 7.7%, 7.8%, and 12.9% for placebo, DAPA 2.5mg, 5mg, and 10mg groups; 5%, 8%, 13%, and 9%; 0.7%, 3.9%, 6.2%, and 6.6%; 7.2% DAPA vs 2.0% placebo % hypoglycemia 2.7%, 1.5%, 0%, and 2.9% in patients in placebo, DAPA 2.5mg, 5mg, and 10mg groups; 3%, 2%, 4%, and 4%; 4.8%, 7.1%, 6.9%, and 7.9% ISMP High Alert Medication – Dispense with Medication Guide Invokana® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 2013. Farxiga™ [package insert. Wilmington, DE: AstraZeneca. 2014.

Place in Therapy – Monotherapy Recent-onset diabetes and mild hyperglycemia (A1c≤7.5%) Metformin is preferred If intolerance or contraindication to metformin SGLT2 inhibitors compared to placebo Decreasing A1c Decrease fasting glucose Guidelines provide no preference May consider SGLT2 inhibitors Renal contraindication so going to be similar to metformin – not a great alternative for these patients Decrease A1c by ~1% Patient centered approach – take into consideration previously mentioned factors, weigh pros and cons of each agent to decide Diabetes Care 2014;37: S14-79. Ferrannini E, et al. Diabetes Care. 2010;33(10):2217-2224.

Place in Therapy – Combination Therapy Initial A1c >7.5% – start dual therapy Target A1c not reached in 3 months with metformin – add second agent No preferred agent to be combined with metformin SGLT2 inhibitors studies have demonstrated improved glycemic control with combination and add-on therapy Metformin Sulfonylurea Thiazolidinedione Insulin Can consider SGLT2 inhibitors in combination with metformin Patient centered approach – take into consideration previously mentioned factors, weigh pros and cons of each agent to decide Some Studies looked at dual and some at triple Insulin was basal or basal/prandial? Bailey, et al. Add-on to metformin in patients inadequately controlled with metformin alone Favorable safety parameters and tolerability Study found improved glycemic control with metformin + SGLT-2 inhibitor Combination is not associated with risk for hypoglycemia Add-on to glimepiride in patients poorly controlled sulfonylurea therapy Significantly improved mean A1C Reduced weight Well-tolerated Add-on to insulin in patients poorly controlled with insulin Sustained effectiveness and stable tolerability Less likely to D.C or require insulin up-titration due to poor glycemic control versus placebo Increased frequency of weight loss and reduced frequency of peripheral edema over time Diabetes Care 2014;37: S14-79. Bailey CJ, et al. Lancet. 2010;375(9733):2223-2233. Strojek K, et al. Abstract 870. EASD 2010. Wilding JPH, et al. Abstract 78-OR. ADA 2010. Bailey CJ et al. Abstract 988-P. ADA 2011.

Patient Centered Approach When Considering SGLT2 Inhibitors Pros Cons Effectiveness independent of insulin Can ↓ A1c by ~1% Combine with other oral anti-diabetics and insulin Low risk for hypoglycemia Small amount of weight loss Small ↓ in blood pressure Adequate renal function required ↑ urinary frequency Electrolyte disturbances ↑ risk of UTIs and vaginal yeast infections Orthostatic hypotension Lipid abnormalities (↑ LDL) Cost Patient centered approach – take into consideration previously mentioned factors, weigh pros and cons of each agent to decide Patient factors: Patient preferences Duration of diagnosis Age Kidney or liver dysfunction Comorbidities Medication factors: Efficacy (A1c lowering) Cost Potential side effects Effects on weight Risk of hypoglycemia Many Considerations to take into account when determining appropriate Drug Therapy: Nonglycemic effects: Effects of individual therapies on CVD risk: HTN, hyperlipidemia A1C: Baseline, Goal, Expected reduction Non-glycemic effects, Duration of DM, Age, Organ function, Comorbidities (Heart failure, Alcoholism, Cognitive function, Dexterity, COST Diabetes Care 2014;37: S14-79.

Assessment Question Which of the following is a counseling point to tell a patient being started on canagliflozin? Will cause significant weight loss Take before the last meal of the day May increase your risk of urinary tract infections Has a high risk of hypoglycemia in combination with metformin Conclusion: (for slide before) Novel mechanism of action: Novel: of a new kind; different from anything seen or known before: a novel idea. Does not mean that this new class is going to “cure” diabetes Ideal place in therapy: add on to metformin Consider individual patient factors and weigh pros/cons Just approved: empagliflozin (Jardiance) Should be taken before the first meal of the day Low likelihood of hypoglycemia unless in combination with another agent that causes hypofglycemia (metformin does not) Will cause a small amount of weight loss. Also, any oral anti-diabetic agent should be used in combination with diet and exercise.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors and their place in therapy Katee Lira, PharmD PGY2 Ambulatory Care Pharmacy Resident St. Vincent Joshua Max Simon Primary Care Center September 18, 2014 I would like to open the floor up for questions at this time. This speaker has no actual or potential conflicts of interest to disclose in relation to this presentation.