2. Understand 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
3. SGLT1: 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.
5. Jung CH, Jang JE, Park JY. Diabetes Metab J 2014;38261-73.
6. Up to 30 years of data on patients with
familial renal glucosuria caused by SGLT2
mutations
Parent compound, phlorizin, was isolated
from apple tree bark
Phlorizin 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.
7. Canagliflozin (Invokana)
100mg and 300mg
Avoid 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.
8. 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.
9. Widely 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.
13. 0
0.2
0.4
0.6
0.8
1
1.2
Canagliflozin
Dapagliflozin
Empagliflozin
0.91
0.5
0.7
1.16
0.7
0.9
A1c(%)Reduction
Low Dose
High Dose
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.
14. 0
10
20
30
40
50
Canagliflozin
Dapagliflozin
Empagliflozin
36
19.9
31
43
24.7
36
FPG(mg/dL)Reduction
Low Dose
High Dose
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.
15. 0
10
20
30
40
50
60
70
canagliflozin
dapagliflozin
48
47
64
51
PPG(mg/dL)Reduction
low dose
high dose
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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Group
Hypoglycemic 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.
23. 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.
24. 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.
25. Drug Dose
Urinary tract
infections
Genital mycotic infections
Female Male
Canagliflozin
100mg 5.9% 10.4% 4.2%
300mg 4.3% 11.4% 3.7%
Dapagliflozin
5mg 5.7% 8.4% 2.8%
10mg 4.3% 6.9% 2.7%
Empagliflozin
10mg 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.
26. 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
28. Drug Dose Change in SCr
(mg/dL)
Change in eGFR
(mL/min/1.73m2)
Canagliflozin 100mg
*Renal impaired
0.02
0.16
-2.3
-3.6
300mg
*Renal impaired
0.03
0.18
-3.4
-4.0
Dapagliflozin 5mg
*Renal impaired
-0.001
0.06
0.8
-4.2
10mg
*Renal impaired
0.001
0.15
0.3
-7.3
Empagliflozin 10mg 0.01 -0.6
25mg
*Renal impaired
0.01
0.11
-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.
29. Osmotic diuresis & volume depletion
Polyuria (including nocturia) resulting in
dehydration, hypovolemia, syncope, etc.
Increased risk if > 75yo, eGFR < 60ml/min or on
loop diuretics
Dose-dependent decrease in blood pressure
Systolic 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.
30. 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.
31. 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.
32. * SGLT2s average A1c reduction = 0.5 – 1 %
Drug Average A1c Reduction
Meglitidines 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.
33. T2DM with adequate renal function
Reduction of < 1% in A1c needed to reach goal
Not a candidate for or inadequate control with:
Metformin
Sulfonylureas
Pioglitazone
DPP-4 inhibitors
Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitor (Canagliflozin and Dapagliflozin) Criteria For Use. VHA. Department of Veterans Affairs; May 2013.
34. 3-drug regimen: not a good candidate for insulin
Increased risk for hypoglycemia
Frail elderly, liver failure, workers with frequent rotation
shifts and occupations, like truck or bus drivers
Unable to master injection technique
Patient 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.
35.
36. 1. 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.
Editor's Notes
My name is Shannon DeGrote and I am one of the PGY-1 pharmacy residents and today I will be presenting on the new class of antidiabetic agents, sodium glucose co-transporter 2s or SGLT2s.
By the end of this presentation my goal is for everyone in this room to understand the mechanism of action of SGLT2s, learn SGLT2s development history, identify the FDA approved SGLT2s, distinguish the differences between these approved SGLT2s, determine their glycemic efficacy, identify the risks and side effects of therapy and lastly to recognize their place in diabetes management.
There are a few sodium-glucose co-transporters located throughout our body. Currently, research has identified 6 SGLTs. However, we will only be focusing on two of these as the others function and mechanism of action is still not completely understood. SGLT1 is primarily located in the brush border of the small intestine where it functions to absorb glucose. However, 10% is located in the kidney, primarily the S2 and S3 segments of renal proximal tubule. Whereas SGLT2 is primarily located in the S1 segment of the proximal renal tubule. The drugs developed were targeted to this SGLT2 as 90% is located within the kidney.
So in a normal functioning cell, SGLT1 and 2 are involved in the movement of glucose, sodium, potassium and water from the proximal tubular lumen to the interstitium and back into the body. More specifically, they are active co-transporters, ATP-dependent proteins involved in moving glucose against a concentration gradient with simultaneous transport of sodium down its concentration gradient. Once reabsorbed from the proximal tubule, glucose is then transported passively into the interstitium through facilitative glucose transporters (GLUTs). The sodium that was reabsorbed along with the glucose is transported by a sodium-potassium pump that shuttles sodium into the interstitum and potassium into the proximal tubule cell. Not only is the movement of glucose sodium and potassium involved, but so is water. Water follows the movement of the glucose and sodium particles via osmosis through the tight junction.
Thus by inhibiting these receptors, sodium and glucose re-absorption is reduced. This can lead to a urinary loss of glucose of 60-80 grams per day or roughtly 200-300kcals per day. However the amount of glucose that is lost is somewhat dependent on the level of glucose in the plasma.
The amount of glucose that is reabsorbed through SGLT2 is dependent on the plasma glucose concentration and the filtration rate of the kidney. SGLT2 serves the body in healthy individuals to reabsorb every glucose molecule that passes through the kidney until the renal glucose threshold is surpassed. This threshold is when the transporter becomes saturated and glucosuria results. SGLT2 becomes saturated at its maximum reabsorption capacity or Tm which is normally reached at 200mg/dL glucose concentration in the plasma in healthy individuals. However, in patients with diabetes the Tm is approximately 20% higher for potentially multiple reasons. One potential explanation is an increase in SGLT2 expression. This may be a maladaption to chronic hyperglycemia and exacerbate it by attempting to curtail the glucosuria.
It is important to realize however that this inhibition of SGLT2 does not prevent all glucose from being reabsorbed, but rather lowers the threshold and reabsorption capacity to near normal levels in adults without diabetes. Hence we only see around 60-80 grams of glucose that is lost in the urine compared to the 180 grams of glucose the kidney filters daily assuming a 100mg/dL plasma glucose concentration in an average adult with healthy kidneys who filters 180 liters of plasma daily.
So idea for this new gliflozin class came from multiple avenues. First, 30 years ago mutations in SGLT2 that cause a relatively benign disease called familial renal glucosuria were discovered. Thus after collecting 30 years of data, targeting this molecule that causes glucosuria was deemed to be a potentially safe option in the treatment of diabetes. Secondly, phlorizin, a member of the chalocone class, was isolated from the root bark of the apple tree in 1835 by a French chemist. Back then, it was used to treat fever and infectious diseases, particularly malaria. Then due to discovery of its ability to induce glucosuria, it then began being used as a renal function test. If phlorizin induced glucosuria that was indicative of a ‘sound kidney.’ Phlorizin was then pursued in development for SGLT2 inhibition due to its selectivity for SGLT2 over SGLT1. However, phlorizin a natural o-glucoside and synthetic o-glucosides were eventually surpassed by c-glucosides for two reasons. First they still had potential to inhibit SGLT1 which can cause glucuse-galatose malabsorption and potential diarrhea. Secondly and more importantly, due to their poor bioavailability. Thus all gliflozins available are C-glucosides with increased bioavailability and selectivity
The three c-glucosidase SGLT2 inhibitors available are cana-, dapa- and empa-gliflozin. There are several others being researched and undergoing trials.
The first to be approved was canagliflozin in January of 2013. It was approved in two dosage strengths, 100 and 300mg. However, 100mg is the maximum dose for CrCl < 45-60ml/min and use is not recommended in CrCl < 30-45ml/min
- Increase in non-fatal stroke?
Dapagliflozin was the second to be FDA approved in January of 2014 also in two dosage strengths with recommendations to avoid use in CrCl < 60 ml/min. However, dapagliflozin was actually the first SGLT2 to complete phase III trials and the first to be presented to the FDA for approval. However, the FDA denied its first application stating the increased incidence of bladder and breast cancer seen in clinical trials warranted further study before approval. Thus after several additional long term studies it was approved a year after canagliflozin. The increased incidence of bladder cancer was 10 cases out of 6045 or 0.17% compared to 1 out of 3512 or 0.1% in placebo/active comparators and the increased incidence of breast cancer was 12 cases in 2693 or 0.45% compared to 3 out of 1439 or 0.45% in placebo/active comparators. The exact relationship between dapagliflozin and these cancers is uncertain as majority of the studies were less than 90 week durations and these cancers typically take years to develop.
Empagliflozin was recently approved by the FDA in August of 2014. Again it was approved at two dosage strengths and is not recommended in CrCl < 45ml/min. Empagliflozin was developed as it is the most selective for the SGLT2 receptor out of the available drugs. Thus it was believed to have the potential to be safer and/or more effective.
So how effective are these medications? On average you can expect a reduction in A1c by 0.5-1%, a reduction in fasting plasma glucose of 15-40mg/dL and a reduction in 2 hour post-prandial glucose of 45-65mg/dL. This reduction in post-prandial glucose levels has to do with the renal glucose threshold. This threshold is much more likely to be surpassed leading to glucose excretion in the urine after meals when blood glucose levels are highest. There is no insulin-dependent mechanism of action with these medications. However, due to their potential to decrease post-prandial glucose levels they are dosed in regards to meals. The first meal due to their potential to cause diuresis and only once daily due to their long half lives.
Also included in the studies efficacy end-points was weight loss due to the loss of glucose in the urine. The amount of weight loss was around 1-4% and widely variable between studies. A recent meta-analysis that pooled all the studies from the three medications found an average loss of 2.37% or 1.74kg overall. However, they noted significant heterogeneity amongst the studies.
So then to break down the glycemic efficacy by drug we see widely varying reductions in both A1c and fasting plasma glucose by drug, dose and whether used as monotherapy or in combination therapy. As you can see here glycemic efficacy from strongest to weakest is canagliflozin, empagliflozin and then dapagliflozin based on A1c. However this superiority of empagliflozin to dapagliflozin is not so clear cut when looking at fasting plasma glucose where you see a more variable reduction in fasting plasma glucose with empagliflozin compared to dapagliflozin.
Moving onto breaking down the glycemic efficacy by dose as well as by regimen, we will start with the first approved SGLT2 inhibitor, canagliflozin. As you can see in this table the glycemic efficacy tends to decrease when used as an adjunct therapy compared to when used alone. You can also see the benefit of increasing the dose from 100mg to 300mg throughout all groups.
So then dapagliflozin, again you see a slight decrease with combination therapy in comparison to monotherapy but not as significant as with canagliflozin. You also see some added benefit with the increased dose from 5mg to 10mg, however again not as significant as with canagliflozin. Presumably due to this lack of significant difference and improved glycemic control with the higher dose of 10mg, many studies did not even include the 5mg dose. Dapagliflozin was studied as third add on treatment with either metformin and sitagliptin or insulin and an oral antidiabetic agent (most often metformin).
Lastly empagliflozin. Similarly to the other two, you can see a decreased response when added as an add on therapy and similarly to dapagliflozin you can see a lack of improved glycemic response with the increased dose from 10mg to 25mg. Potentially even less of a dose response than dapagliflozin. To note in these studies, empagliflozin was studied as a third add on medication with metformin and a sulfonylurea.
To summarize, SGTL2 inhibitors glycemic efficacy is highest as monotherapy with significant differences between the three approved medications. Canagliflozin produces the most significant A1c reduction at both high and low dose in comparison to dapa and empagliflozin. Empagliflozin is marginally better than dapagliflozin at reducing A1c. Overall, SGTLT2 inhibitors lower can be expected to lower A1c by 1 to one half a percent.
The same goes with reduction in fasting plasma glucose, however empagliflozin shows a bit clearer superiority over dapagliflozin. As mentioned previously, however, when looking at combination therapy empagliflozin has widely varying reductions in FPG with the highest in monotherapy and lowest around a 13 point reduction when added to insulin therapy.
Post prandial reductions were reported in both canagliflozin and dapagliflozin but not in empagliflozin trials. A post prandial reduction of 48 with low dose and 64 with high dose for canagliflozin is an average based on three trials in which canagliflozin was used as monotherapy as well as combination therapy. A post prandial reduction of 47 with low dose and 51 with high dose for dapagliflozin was based on one trial in which dapagliflozin was used in combination with glimepiride or pioglitazone.
Monotherapy: placebo 2.6%
Add-on metformin: 1.6% with metformin alone
Add-on sulfonylurea: 5.8% with sulfonylurea alone
Add-on insulin: 34.3% minor and 2.5% major
Add on glimepiride: in comparison to placebo (glimepiride alone) with 2.1% minor and 0% major
Add on insulin: in comparison to placebo (insulin +/- OADs alone) with 34% minor and 0.5% major
Monotherapy: 0.4% with placebo as well
Add-on metformin: 0.5% minor
Add-on insulin : 20.6% minor
Add-on 3 drug: 8.4% minor
By understanding this mechanism of action and the other consequences of inhibiting glucose reabsorption, such as reduction of sodium and water reabsorption as well as potential reduced excretion of potassium, one begin to hypothesize the potential side effects of this class of medications.
Avoid use in CrCl <45-60ml/min
Dose-dependent decrease in eGFR (~2-6ml/min)
Pre-renal, not direct renal injury
Volume depletion 1-3%
3-8% if >75yo, eGFR<60, or on loop diuretics
Glycemic efficacy declines with decreased renal function (one study done with canagliflozin in CKD with baseline eGFRs of 30-50ml/min saw an A1c reduction of 0.33% with 100mg and 0.44% with 300mg after 26 weeks. Roughly 88% of patients were on one or more anti-diabetic medications of which 66% was insulin. So to put this in perspective compared to those with normal renal function a reduction of 0.62 to 0.91% would be expected to be seen in combination therapy with or without insulin)
However, improves overtime (~1-3ml/min)
Helps prevent and improve albuminuria
Decrease in albumin/creatinine ratio (ACR) leading to delayed progression of albuminuria
This study enrolled subjects with a baseline eGFR of 30-50ml/min/1.73m2
Avoid use in CrCl <45-60ml/min
Dose-dependent decrease in eGFR (~2-6ml/min)
Pre-renal, not direct renal injury
Volume depletion 1-3%
3-8% if >75yo, eGFR<60, or on loop diuretics
Glycemic efficacy declines with decreased renal function
However, improves overtime (~1-3ml/min)
Helps prevent and improve albuminuria
Canagliflozin 4.5-10% which is approximately a 5-10mg/dL change
HDL 1.5 to 3.6% or approximately 2-6mg/dL
Adequate renal function: 45-60ml/min
Inadequate control on monotherapy with metformin (max dose), sulfonylurea (50% max), pioglitazone (max), or DPP-4 inhibitor
Inadequate control on monotherapy with metformin (max dose), sulfonylurea (50% max), pioglitazone (max), or DPP-4 inhibitor
