1. Dr Shahjada Selim
Assistant Professor
Department of Endocrinology
Bangbandhu Sheikh Mujib medical University, Dhaka
Dapagliflozin:
A novel insulin-independent
approach to remove excess glucose
5. Normal renal glucose handling1–3
SGLT, sodium-glucose co-transporter.
1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35;
3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21.
SGLT2
Glucose
Majority of glucose is
reabsorbed by SGLT2
(90%)
Proximal tubule
Remaining glucose is
reabsorbed by SGLT1
(10%)
Minimal to no
glucose excretion
Glucose
filtration
6. Dapagliflozin
Proximal tubule
Glucose
filtration
1. FORXIGA Summary of Product Characteristics
Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule1
SGLT2
Glucose
Dapagliflozin
SGLT2
Dapagliflozin
Increased
urinary glucose
excretion
7. The benefits of dapagliflozin’s novel
mechanism of action
Dapagliflozin offers an insulin-
independent mechanism that can be
used as add-on therapy1,4
1. Bailey CJ, et al. Lancet 2010;375:2223–33;
2. FORXIGA Summary of Product Characteristics
8. The benefits of dapagliflozin’s novel
mechanism of action
Dapagliflozin inhibition of SGLT2 results in
daily urinary glucose excretion of
approximately 70g,2 providing:
Significant and sustained HbA1c reductions
versus placebo when added to metformin1,3
Secondary benefit of weight loss1
1.Bailey CJ, et al. Lancet 2010;375:2223–33;
2. FORXIGA Summary of Product Characteristics
3.Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association,
San Diego, California, 24–28 June, 2011
9. Side Effects
Increased susceptibility
to infection
Polyuria
Hypotension
Hyperkalemia
Impaired renal function
Increase in LDL
10. Urinary tract infection risks
likely to increase as…
Increased glucose in urine
Genital mycotic > urinary tract infections
(UTIs)
At increased risk:
Females
11-15% F > 1-8% M
Dose-independent
Vasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.
11. Infections
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) packageinsert. 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. Kidney Function
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.
14. Dapagliflozin: Reductions in HbA1c were sustained over 102 weeks
Data are mean change from baseline after adjustment for baseline value. Data after rescue are excluded.Analyses were obtained by
longitudinal repeated measures analyses. CI, confidence interval.
Adapted from Bailey CJ et al. Poster #988-P. Poster presented at 71st Scientific Sessions of the American Diabetes Association, San Diego, California, June
24–28, 2011.
Study week
–1.2
–0.8
–0.6
–0.4
0.2
0 16 37 50 63 76 10289
0.0
HbA1c(%)
meanchangefrombaseline
8 24
Primary endpoint
–1.0
–0.2
–5
0
–10
Dapagliflozin 10 mg +
metformin
(Mean baseline HbA1c 7.92% [63
mmol/mol])
Placebo + metformin
(Mean baseline HbA1c 8.11% [65
mmol/mol])
(n=133)
(n=132)
HbA1c(mmol/mol)
meanchangefrombaseline
+0.02%
(0.2
mmol/mol)
(95% Cl,
–0.20 to 0.23%;
n=28)
–0.78%
(–8.5 mmol/mol)
(95% Cl,
–0.97 to –0.60%;
n=57)
0.80%
(8.8 mmol/mol)
difference
15. 1. Ferrannini E et al. Diabetes Care 2010;33:2217–2224. 2. Bailey CJ et al. Lancet 2010;375:2223–2233.
3. Strojek K et al. Diabetes Obes Metab 2011;13:928–938. 4. Wilding JPH et al. Ann Intern Med 2012;156:405–415.
Dapagliflozin: Consistent reduction in HbA1c at Week 24 across studies
Baseline HbA1c:
7.91%; 63 mmol/mol
MeanchangeinHbA1c(%)
–0.23
(-3 mmol/mol)
–0.89*
(-10 mmol/mol)
–0.84*
(-9 mmol/mol)
–0.30
(-3 mmol/mol)
–0.82*
(-9 mmol/mol)
–0.13
(-1 mmol/mol)
–0.96*
(-10 mmol/mol)
–0.39
(-4 mmol/mol)
Baseline HbA1c:
8.05%; 64 mmol/mol
Baseline HbA1c:
8.11%;
65 mmol/mol
Baseline HbA1c:
8.53%; 70 mmol/mol
Add-on to a
SU3
Add-on to metformin2Monotherapy1 Add-on to insulin4
These data are taken from different studies and the results should not be compared across studies.
*Statistically significant vs. placebo using Dunnett’s correction.SU, sulphonylurea.
Dapagliflozin (10 mg)
Placebo
p<0.0001 p<0.0001 p<0.0001 p<0.001
16. Dapagliflozin: secondary benefit of weight loss over 102
weeks
Weight loss at 24 weeks, with decreased waist circumference is consistent with a reduction of body-fat mass 1
In a separate study, weight loss was mainly attributable to reduction in body fat mass rather than loss of fluid or lean
tissue3 #
Adjustedmeanchange
frombaselinebodyweight(kg)
24 weeks (LOCF analysis)1
–1.70 kg
(n=95)
95% Cl
(-2.48 to -0.91)
–2.9 kg
(n=133)
95% CI
(-3.3 to -2.4)
–0.9 kg
(n=136) 95%CI
-1.4 to -0.4
2.0 kg
difference
p<0.0001
+1.36 kg
(n=73)
95% Cl
(0.53 to 2.20)
3.1 kg
difference
p value not
calculated
Data are mean change from baseline after adjustment for baseline value (mean baseline weight: dapagliflozin 86.3 kg, placebo 87.7 kg).
24-week data are based on LOCF analysis excluding data after rescue; 102-week data are based on longitudinal repeated measures analysis and include data
after rescue.
# As measured by dual energy absorptiometry at 24 weeks
1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. Bailey CJ, et al. Poster 988-P. Poster presented at 71st Scientific Sessions of the American Diabetes
Association, San Diego, California, June 24–28, 2011; 3. Bolinder J, et al. J Clin Endocrinol Metab 2012;97:1020–31.
102 weeks (repeated measures analysis)2
Dapagliflozin 10 mg
+ metformin
Dapagliflozin 10 mg
+ metformin
Placebo
+ metformin
Placebo
+ metformin
Adapted from Bailey CJ, et al. (2010) & Bailey CJ, et al. (2011)
17. Reductions in HbA1c with insulin + dapagliflozin
compared with insulin + placebo at 24 weeks
1. Wilding J, et al. Ann Intern Med 2012;156:405–415.
2. FORXIGA™. Summary of product characteristics.
Adapted from Wilding J, et al. 2012
Last observation carried forward (LOCF). Data are adjusted mean change from baseline. Mean HbA1c at baseline were 8.47% (69
mmol/mol) for insulin + placebo and 8.57% (70 mmol/mol) for insulin + dapagliflozin 10mg.
Consider a reduction in insulin dose on commencement of dapagliflozin to reduce the risk of hypoglycaemia2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Adjustedmeanchangefrom
baselineHbA1c(%)
Adjustedmeanchangefrom
baselineHbA1c(mmol/mol)
Dapagliflozin 10 mg +
insulin
Placebo +
insulin
–0.96%
(–10.5 mmol/mol)
(n=194)
–0.39%
(–4.3 mmol/mol)
(n=193)
0.57% (6.2 mmol/mol)
difference
(95% CI, –0.72 to –0.42%)
p<0.001
-10
-5
0
18. Uptitration of insulin dosing is less pronounced in patients treated
with insulin + dapagliflozin compared with insulin + placebo ± OADs
1. Wilding JPH et al. Ann Intern Med 2012;156:405–415.
2. FORXIGA™. Summary of product characteristics..
Dapagliflozin
190
Change in total daily insulin dose (units)
from baseline1:
At 24 weeks
placebo + insulin – 8% increase
dapagliflozin + insulin – 1.5% decrease
At 48 weeks
placebo + insulin – 14% increase
dapagliflozin + insulin – 1% decrease
Patients needing rescue therapy or
withdrawn from study for not achieving
glycaemic targets:1
Placebo + insulin – 42.8%
dapagliflozin 10mg + insulin – 15.3%
Baseline mean daily insulin dose (units):
• Insulin + placebo = 73.7
• Insulin + dapagliflozin 10mg = 78.0
• Consider a reduction in insulin dose on
commencement of dapagliflozin to
reduce the risk of hypoglycaemia2
20. 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) packageinsert. 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.
21. 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 secretagogues
SGLT2is 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.
22. 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.
27. 1.1 Dapagliflozin in a dual therapy regimen in
combination with metformin is recommended as
an option for treating type 2 diabetes, only if it is
used as described for dipeptidyl peptidase-4
(DPP-4) inhibitors inType 2 diabetes: the
management of type 2 diabetes (NICE clinical
guideline 87).
NICE TA288
http://publications.nice.org.uk/dapagliflozin-in-combination-
therapy-for-treating-type-2-diabetes-ta288
28. 1.2 Dapagliflozin in combination with insulin with or without
other antidiabetic drugs is recommended as an option for
treating type 2 diabetes.
1.3 Dapagliflozin in a triple therapy regimen in combination with
metformin and a sulfonylurea is not recommended for treating
type 2 diabetes, except as part of a clinical trial.
NICE TA288
http://publications.nice.org.uk/dapagliflozin-in-combination-
therapy-for-treating-type-2-diabetes-ta288
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.
7
8
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
However, improves overtime (~1-3ml/min)
Helps prevent and improve albuminuria
14
16
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).
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