sglt2 endocrine cme grand rounds final

1

Sodium Glucose Co-Transporter 2(SGLT2s)

Shannon DeGrote, PharmDPGY-1 Pharmacy Resident

01/08/2015

ObjectivesUnderstand mechanism of action of SGLT2s

Learn SGLT2 development history

Identify FDA-approved SGLT2s

Distinguish differences between approved SGLT2s

Determine glycemic efficacy

Identify risks and side effects of therapy

Recognize place in diabetes management

The KidneySGLT1: 10%

Brush border of small intestine

SGLT2: 90%Glucose re-absorption at proximal tubule

1. Jung CH, Jang JE, Park JY. Diabetes Metab J 2014;38261-73.2. Fujita Y, Inagaki Y. J Diabetes Invest. 2014;5:265-75.

SGLT1/2

Involves movement ofGlucose

Sodium

Potassium

Water

Urinary loss of glucose 60-80g/day

200-300kcal/day

1. Jung CH, Jang JE, Park JY. Diabetes Metab J 2014;38261-73.2. Fujita Y, Inagaki Y. J Diabetes Invest. 2014;5:265-75.

Renal Glucose Threshold (RTG)

Jung CH, Jang JE, Park JY. Diabetes Metab J 2014;38261-73.

SGLT2 ClassUp to 30 years of data on patients with familial

renal glucosuria caused by SGLT2 mutationsParent compound, phlorizin, was isolated from

apple tree barkPhlorizin has 10 times

the selectivity for SGLT2 > SGLT1

Phlorizin is a natural O-glucoside

1. Fujita Y, Inagaki Y. J Dibetes Invest. 2014;5:265-75.2. Chen LH, Leung PS. Diabetes Obes Metab. 2013;15:392-402.

Three SGLT2s AvailableCanagliflozin (Invokana)

100mg and 300mgAvoid in CrCl <30- 45ml/min

Dapagliflozin (Farxiga)5mg and 10mg

Avoid in CrCl < 60ml/min

Empagliflozin (Jardiance)10 and 25mg

Avoid in CrCl < 45ml/min

CANAGLIFLOZIN

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.3. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.

Glycemic Efficacy

Average reduction of:

A1c: 0.5-1%

Fasting plasma glucose (FPG): 15-40mg/dL

2-hour post-prandial glucose (PPG): 45-65mg/dL

***Take before first meal of the day***

Weight loss 1-4%

Vasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.

Glycemic Efficacy of SGLT2sWidely varying reductions in average HbA1c and FPG depending on drug, dose and whether used as monotherapy or combination therapy

Drug HbA1c Reduction FPG Reduction

Canagliflozin -0.73 to -1.08% -22 to -47mg/dL

Dapagliflozin -0.52 to -0.59% -16 to -28mg/dL

Empaglifozin -0.62 to -0.66% -13 to -36mg/dL

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.3. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.4. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58.5. Zang M, Zhang L, Wu B, et al. Diabetes Metab Res Rev. 2014;30:204-21.6. Liakos A, Karagiannis T, Athanasiadou E, et al. Diabetes Obes Metab. 2014; 16: 984-93.

Canagliflozin

GroupA1c Reduction FPG Reduction

100mg 300mg 100mg 300mg

Monotherapy -0.91 -1.16 -36 -43

Add-on metformin

-0.62 -0.77 -30 -40

Add-on sulfonylurea

-0.74 -0.83 -30 -47

Add-on insulin -0.65 -0.73 -23 -29

Add-on 3 drug regimen

-0.71 -0.92 -22 -35

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58.

DapagliflozinGroup

A1c Reduction FPG Reduction5mg 10mg 5mg 10mg

Monotherapy -0.5 -0.7 -19.9 -24.7

Add-on metformin

-0.4 -0.5 -15.5 -17.5

Add-on glimepiride

-0.5 -0.7 -19.3 -26.5

Add-on pioglitazone

-0.4 -0.6 -19.5 -24.1

Add-on insulin -0.5 -0.6 -- -25


-- -0.48 -- -27.9

1. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.2. Zang M, Zhang L, Wu B, et al. Diabetes Metab Res Rev. 2014;30:204-21.

Empagliflozin

GroupA1c Reduction FPG Reduction

10mg 25mg 10mg 25mg

Monotherapy -0.7 -0.9 -31 -36

Add-on metformin

-0.6 -0.6 -26 -29

Add-on pioglitazone

-0.5 -0.6 -23 -28

Add-on insulin -0.5 -0.7 -12.9 -17.9


-0.6 -0.6 -29 -29

1. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.2. Liakos A, Karagiannis T, Athanasiadou E, et al. Diabetes Obes Metab. 2014; 16: 984-93.

Monotherapy: A1c Reductions

CanagliflozinDapagliflozin

Empagliflozin

0

0.2

0.4

0.6

0.8

1

1.2

0.91

0.5

0.7

1.16

0.7

0.9

Low DoseHigh Dose

A1c

(%

) Red

uctio

n


Monotherapy: FPG Reductions

CanagliflozinDapagliflozin

Empagliflozin

0

5

10

15

20

25

30

35

40

45

36

19.9

31

43

24.7

36

Low DoseHigh Dose

FPG

(m

g/dL

) Red

uctio

n


Postprandial Reductions

canagliflozindapagliflozin

0

10

20

30

40

50

60

70

4847

64

51

low dosehigh dose

PPG

(m

g/dL

) Red

uctio

n

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.3. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58.4. Zang M, Zhang L, Wu B, et al. Diabetes Metab Res Rev. 2014;30:204-21.

Weight Loss

Group Low Dose (kg) High Dose (kg)

Canagliflozin 2.2 3.3

Canagliflozin + Insulin 1.9 2.4

Dapagliflozin 2.2 2

Dapagliflozin + insulin 1 1.7

Empagliflozin 2.5 2.8

Empagliflozin + insulin 3 3


Hypoglycemia

Insulin-independent mechanism of action

Low risk when used as monotherapy

Comparable to that of metformin or sitagliptin

Increased risk with insulin and insulin secretagogs

SGLT2s lower the renal reabsorption of glucose

threshold without completely inhibiting it

Renal threshold of < 70mg/dL

1. Chen LH, Leung PS. Diabetes Obes Metab. 2013;15:392-402.2. Jung CH, Jang JE, Park JY. Diabetes Metab J 2014;38261-73.3.. Fujita Y, Inagaki Y. J Diabetes Invest. 2014;5:265-75.

Canagliflozin Hypoglycemia

Group

Hypoglycemic Events

Minor Major

100mg 300mg 100mg 300mg

Monotherapy 3.6% 3.0% -- --

Add-on metformin 4.1% 4.3% 0.3% 0.3%

Add-on sulfonylurea 4.1% 12.5% -- --

Add-on insulin 47.5% 45.8% 1.8% 2.7%

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58.

Dapagliflozin Hypoglycemia

Group

Hypoglycemic Events

Minor Major

5mg 10mg 5mg 10mg

Monotherapy 0% 0% 0% 0%

Add-on metformin 1.5% 0.7% 0% 0%

Add-on glimepiride 5.5% 6.0% 0% 0%

Add-on pioglitazone 2.1% 0% 0% 0%

Add-on insulin 43.4% 40.3% 0.5% 0.5%

1. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.2. Zang M, Zhang L, Wu B, et al. Diabetes Metab Res Rev. 2014;30:204-21.

Empagliflozin Hypoglycemia

Group

Hypoglycemic Events

Minor Major

10mg 25mg 10mg 25mg

Monotherapy 0.4% 0.4% 0% 0%

Add-on metformin 1.8% 1.4% 0% 0%

Add-on pioglitazone 1.2% 2.4% 0% 0%

Add-on insulin 19.5% 27.1% 0% 1.3%

Add-on 3 drug regimen 16.1% 11.5% 0% 0%

1. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.2. Liakos A, Karagiannis T, Athanasiadou E, et al. Diabetes Obes Metab. 2014; 16: 984-93.

SGLT2 Add-on Insulin Therapy

GroupHypoglycemic Events

Minor Major

100mg 300mg 100mg 300mg

Canagliflozin 47.5% 45.8% 1.8% 2.7%

Dapagliflozin 43.4% 40.3% 0.5% 0.5%

Empagliflozin 19.5% 27.1% 0% 1.3%


Side Effects

Infection risk

Polyuria

Hypotension

Hyperkalemia

Impaired renal function

Increase in LDL

Infection Risk

Increased glucose in urine

Genital mycotic > urinary tract infections (UTIs)

At increased risk:Females

11-15% F > 1-8% M

Uncircumcised males

Dose-independent


Infection Risk Odds Ratios

Infection Placebo Active-comparators

UTI 1.34[1.03 – 1.74]

1.42[1.06 – 1.90]

Genital Mycotic 3.5[2.46 – 4.99]

5.06[3.44 – 7.45]


Infections

Drug Dose Urinary tract infections

Genital mycotic infections

Female Male

Canagliflozin100mg 5.9% 10.4% 4.2%

300mg 4.3% 11.4% 3.7%

Dapagliflozin5mg 5.7% 8.4% 2.8%

10mg 4.3% 6.9% 2.7%

Empagliflozin10mg 9.3% 5.4% 3.1%

25mg 7.6% 6.4% 1.6%


Kidney Function

Avoid use in CrCl < 30-60ml/min

Dose-dependent decrease in eGFR (2-6ml/min)However, improves overtime (1-3ml/min)

Renoprotective effects?

Glycemic efficacy declines with decreased renal function

Canagliflozin Change in eGFR

Yale JF, Bakris G, Cariou B. Diab Ob Metab 2013;15:463-73

Kidney FunctionDrug Dose Change in SCr

(mg/dL)Change in eGFR

(mL/min/1.73m2)Canagliflozin 100mg

*Renal impaired0.020.16

-2.3-3.6

300mg *Renal impaired

0.030.18

-3.4-4.0

Dapagliflozin 5mg*Renal impaired

-0.0010.06

0.8-4.2

10mg*Renal impaired

0.0010.15

0.3-7.3

Empagliflozin 10mg 0.01 -0.6

25mg*Renal impaired

0.010.11

-1.4-2.8


Kidney Function

Osmotic diuresis & volume depletionPolyuria (including nocturia) resulting in dehydration, hypovolemia, syncope, etc.

Increased risk if > 75yo, eGFR < 60ml/min or on loop diuretics

Dose-dependent decrease in blood pressureSystolic BP 3-6mmHg

Diastolic BP 1-2mmHg

1. Vasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.2. Fujita Y, Inagaki Y. J Diabetes Invest. 2014;5:265-75.

Dyslipidemia

Dose-dependent increase in LDL

Canagliflozin: 4.5 – 10%

Dapagliflozin: 1 – 9.5%

Empagliflozin: 4.6 – 6.5%

Increase in HDL 1.5 – 5%

Decrease in TG -16% - +4%1. Chen LH, Leung PS. Diabetes Obes Metab. 2013;15:392-402.2. Yang XP, Lai D, Zhong XY, et al. Eur J Clin Pharmacol. 2014; 70:1149-58.3. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.4. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.

Pregnancy and Lactation

Category C

Fetal renal development and maturation

2nd and 3rd Trimesters

Can pass through breast milk

Development through 2 years of age

1. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.2. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.3. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.

Current Therapies Glycemic Efficacy

* SGLT2s average A1c reduction = 0.5 – 1 %

Drug Average A1c ReductionMeglitidines 0.5-1.5%Biguanides 1-2%Sulfonylureas 1-2%TZDs 1-1.5%Alpha-glucosidase inhibitors 0.5-1%DPP-4s 0.5-1%GLP-1s 1-1.5%Amylin Agonists 0.5-1%

1. PL detail-document. Drugs for type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter. Oct 2014.2. ADA. Diabetes care. Diabetes Care 2012;34(suppl 1):S18. Table 10.

Place in VA DM Management: Non-Formulary Criteria

T2DM with adequate renal function Reduction of < 1% in A1c needed to reach goalNot a candidate for or inadequate control with:

MetforminSulfonylureasPioglitazoneDPP-4 inhibitors

Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor (Canagliflozin and Dapagliflozin) Criteria For Use. VHA. Department of Veterans Affairs; May 2013.

Place in VA DM Management: Non-Formulary Criteria

3-drug regimen: not a good candidate for insulinIncreased risk for hypoglycemia

Frail elderly, liver failure, workers with frequent rotation shifts and occupations, like truck or bus drivers

Unable to master injection techniquePatient refuses insulin

Dapagliflozin: No active or history of bladder cancer

Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor (Canagliflozin and Dapagliflozin) Criteria For Use. VHA. Department of Veterans Affairs; May 2013.

Questions?

References1. Jung CH, Jang JE, Park JY. A novel therapeutic agent for type II diabetes mellitus: SGLT2 inhibitor. Diabetes Metab J 2014;38261-

73.2. Fujita Y, Inagaki Y. Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2

diabetes: clinical data and mechanism of action. J Dibetes Invest. 2014;5:265-75.3. Chen LH, Leung PS. Inhibition of the sodium glucose cotransporter 2 its beneficial action and potential combination therapy for

type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:392-402.4. Invokana® (capagliflozin) package insert. Titusville (NJ): Janssen Pharmaceuticals; May 2014.5. Farxiga® (dapagliflozin) package insert. Prineton (NJ): Bristol-Myers Squibb; Aug 2014.6. Jardiance® (empagliflozin) package insert. Ridgefield (CT): Boehringer Ingelheim; Aug 2014.7. Vasilakou D, Karaglannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes systematic

review and meta-analysis. Ann Intern Med. 2013;159:262-74.8. Yang XP, Lai D, Zhong XY, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes systematic review and meta-

analysis. Eur J Clin Pharmacol. 2014; 70:1149-58.9. Zang M, Zhang L, Wu B, et al. Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized

controlled trials. Diabetes Metab Res Rev. 2014;30:204-21.10. Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes systematic review and

meta-analysis. Diabetes Obes Metab. 2014; 16: 984-93.11. Yale JF, Bakris G, Cariou B. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diab

Ob Metab 2013;15:463-73.12. Canagliflozin (Invokana) Drug Monograph. Washington, DC: Pharmacy Benefits Management Services, Medical Advisory Panel

and VISN Pharmacist Executives, Veterans Health Administration, Department of Veterans Affairs; July 2013. 13. Dapagliflozin (Farxiga) Drug Monograph. Washington, DC: Pharmacy Benefits Management Services, Medical Advisory Panel

and VISN Pharmacist Executives, Veterans Health Administration, Department of Veterans Affairs; Sept 2014. 14. PL detail-document. Drugs for type 2 diabetes. Pharmacist’s Letter/Prescriber’s Letter. Oct 2014.15. ADA. Diabetes care. Diabetes Care 2012;34(suppl 1):S18. Table 10. 16. Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor (Canagliflozin and Dapagliflozin) Criteria For Use. Washington, DC:

Pharmacy Benefits Management Services, Medical Advisory Panel and VISN Pharmacist Executives, Veterans Health Administration, Department of Veterans Affairs; May 2013.

sglt2 endocrine cme grand rounds final

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