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?