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Dr Shahjada SelimAssistant Professor
Department of EndocrinologyBangbandhu Sheikh Mujib medical University, Dhaka
Dapagliflozin: A novel insulin-independent approach to remove excess
glucose
ADA Diabetes Management Algorithm 2015
Three SGLT2is Available
Canagliflozin (Invokana) 100mg and 300mg
Dapagliflozin (Dapazin/Farxiga) 5mg and 10mg
Empagliflozin (Jardiance) 10 and 25mg
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.
How do they work?
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
Glucosefiltration
Dapagliflozin
Proximal tubule
Glucosefiltration
1. FORXIGA Summary of Product Characteristics
Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule1
SGLT2
Glucose
Dapagliflozin
SGLT2Dapagliflozin
Increased urinary glucose
excretion
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
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 Characteristics3.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
Side Effects
Increased susceptibility to infection Polyuria Hypotension Hyperkalemia Impaired renal function Increase in LDL
Urinary tract infection risks likely to increase as…
Increased glucose in urine Genital mycotic > urinary tract
infections (UTIs) At increased risk:
Females11-15% F > 1-8% M
Dose-independentVasilakou D, Karaglannis T, Athanasiadou E, et al. Ann Intern Med. 2013;159:262-74.
Infections
Drug DoseUrinary
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.
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.
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
HbA 1
c (%
)m
ean
chan
ge fr
om b
asel
ine
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 (m
mol/m
ol)m
ean change from baseline
+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
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
Mean change in HbA
1c(%)
–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
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 tissue 3 #
Adjusted mean change
from b
aselin
e body
weigh
t (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 differencep 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)
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
Adju
sted
mea
n ch
ange
from
ba
selin
e Hb
A 1c
(%)
Adjusted mean change from
baseline HbA
1c (mm
ol/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
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..
Dapagliflozin190
Change in total daily insulin dose (units) from baseline1:At 24 weeksplacebo + insulin – 8% increase dapagliflozin + insulin – 1.5% decrease At 48 weeksplacebo + 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
DapagliflozinGroup A1c Reduction (%) FPG Reduction
(mg/dl)5mg 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 pioglitazon
e-0.4 -0.6 -19.5 -24.1
Add-on insulin
-0.5 -0.6 -- -25
Add-on 3 drug
regimen-- -0.48 -- -27.91. 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.
Weight Loss
Group Low Dose (kg)
High Dose (kg)
Canagliflozin 2.2 3.3Canagliflozin +
Insulin 1.9 2.4Dapagliflozin 2.2 2
Dapagliflozin + insulin 1 1.7
Empagliflozin 2.5 2.8Empagliflozin +
insulin 3 31. 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 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.
Dapagliflozin: Hypoglycemia
GroupHypoglycemic EventsMinor Major
5mg 10mg 5mg 10mgMonother
apy 0% 0% 0% 0%
Add-on metformin 1.5% 0.7% 0% 0%
Add-on glimepirid
e5.5% 6.0% 0% 0%
Add-on pioglitazo
ne2.1% 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.
Evidences…..
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 in Type 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
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
THANKS
Questions?