1 Sodium Glucose Co-Transporter 2 (SGLT2s) Shannon DeGrote, PharmD PGY-1 Pharmacy Resident 01/08/2015
Aug 07, 2015
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
Add-on 3 drug regimen
-- -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
Add-on 3 drug regimen
-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
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.
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
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.
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
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.
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%
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.
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
Vasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.
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]
Vasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.
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%
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.
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
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.
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.