1. 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.

2. 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

3. 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:

4. 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:
Glucosuria
Chao EC, et al. Nat Rev Drug Discovery. 2010;9:

5. 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.

6. 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 %)
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: (for weight reduction)
Stenlof K, et al. Diabetes Obes Metab. Published online January 24, (BP and A1c reduction)
List JF, et al. Diabetes Care. 2009;32:
Stenlof K, et al. Diabetes Obes Metab. Published online January 24, 2013.
Invokana® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc
Farxiga™ [package insert. Wilmington, DE: AstraZeneca

7. 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
Farxiga™ [package insert]. Wilmington, DE: AstraZeneca
Jardiance® [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc

8. 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
Farxiga™ [package insert. Wilmington, DE: AstraZeneca

9. 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):

10. 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):
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.

11. 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.

12. 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.

13. 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.