uk/tb/0213/0017a february 2013 new treatment options dr craig parkinson

UK/TB/0213/0017a February 2013

New treatment options

Dr Craig Parkinson


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: A novel insulin-independent approach to remove excess glucose

Proximal tubule

Glucosefiltration

1. FORXIGA Summary of Product Characteristics

Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule1

SGLT2

Glucose

Dapagliflozin

SGLT2

Dapagliflozin

Increased urinary glucose

excretion

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

• 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. List JF, et al. Diabetes Care 2009;32:650–7; 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, 20114. FORXIGA Summary of Product Characteristics


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

1c

(%)

mean c

hang

e f

rom

base

line

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)

HbA

1c (m

mol/m

ol)

mean ch

ang

e fro

m b

ase

line

+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


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 #

Adju

sted m

ean c

hange

from

base

line b

ody w

eig

ht

(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

Adj

uste

d m

ean

chan

ge fr

om

base

line

HbA

1c(%

)A

djusted mean change from

baseline H

bA1c (m

mol/m

ol)

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 ± oral antidiabetic drugs

• 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

1. Wilding JPH et al. Ann Intern Med 2012;156:405–415. 2. FORXIGA™. Summary of product characteristics..

Dapagliflozin

190


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 c

hang

e in H

bA

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)




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


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).

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


Tresiba® – A new basal insulin for adult patients with type 1

and type 2 diabetes


Half-life of insulin degludec is twice as long as that of insulin glargine

Insulin degludec Insulin glargine

0.4 U/kg 0.6 U/kg 0.8 U/kg 0.4 U/kg 0.6 U/kg 0.8 U/kg

Half-life (hours) 25.9 27.0 23.9 11.8 14.0 11.9

Mean half-life 25.4 12.5

*Insulin glargine was undectable after 48 hoursResults from patients with type 1 diabetesIDeg, insulin degludec; IGlar, insulin glargineHeise et al. Diabetologia 2011;54(Suppl. 1):S425

*

IDeg 0.8 U/kgIGlar 0.8 U/kg


70

40H

bA

1c

(mm

ol/m

ol)

65

0

35

50

55

60

75

45

Insulin-naïve T2D: HbA1c and FPG over timeBEGIN® ONCE LONG

Mean±SEM; full analysis set (FAS); last observation carried forward (LOCF)Comparisons: estimates adjusted for multiple covariatesZinman et al. Diabetes Care 2012;35:2464–71

0.0

Treatment difference: non-inferior

Time (weeks)

Treatment difference: –0.43 mmol/L, p<0.05

0.0

Time (weeks)

IDeg OD (n=773)IGlar OD (n=257)

26 26


Insulin-naïve T2D: confirmed hypoglycaemiaBEGIN® ONCE LONG

Severe hypoglycaemia: IDeg, 0.00 events/PYE; IGlar, 0.02 events/PYESAS; LOCF; Comparisons: estimates adjusted for multiple covariatesPYE, patient-years of exposureZinman et al. Diabetes Care 2012; 35:2464–71


18% lower rate with IDeg (ns)

Time (weeks)

IDeg: 1.52 events/PYEIGlar: 1.85 events/PYE


Insulin-naïve T2D: nocturnal confirmed hypoglycaemiaBEGIN® ONCE LONG

SAS; LOCFComparisons: estimates adjusted for multiple covariatesZinman et al. Diabetes Care 2012; 35:2464–71

36% lower rate with

IDeg, p<0.05

Time (weeks)




70

40H

bA

1c

(mm

ol/m

ol)

65

0

35

50

55

60

75

45

Treatment difference: non-inferior

Basal–bolus in T2D: HbA1c and FPG over time BEGIN® BB T2D

IDeg OD + IAsp (n=744)IGlar OD + IAsp (n=248)

Mean±SEM; FAS; LOCF; IAsp, insulin aspart Comparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012;379:1498–507

Treatment difference: –0.29 mmol/L (ns)

Time (weeks) Time (weeks)

0.0 0.026 26


Basal–bolus in T2D: confirmed hypoglycaemiaBEGIN® BB T2D


Severe hypoglycaemia: IDeg, 0.06 events/PYE; IGlar, 0.05 events/PYESAS; LOCF; Comparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012;379:1498–507

18% lower rate with

IDeg, p=0.0359

Time (weeks)



Basal–bolus in T2D: confirmed nocturnal hypoglycaemiaBEGIN® BB T2D


SAS; LOCFComparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012; 379:1498–507

25% lower rate with

IDeg, p=0.0399

Time (weeks)



Based on the long duration of action and flat profile insulin degludec can be administered at any time of the day


Flexible vs Fixed dosing: nocturnal confirmed hypoglycaemiaBEGIN® FLEX T2D

23% lower rate with IDeg Flexible than with

IGlar (ns)

18% higher rate with IDeg Flexible than with

IDeg Fixed (ns)

SAS; LOCFComparisons: estimates adjusted for multiple covariatesBirkeland et al. IDF 2011:P-1443; Bain et al. IDF 2011:O-0508; Birkeland et al. Diabetologia 2011;54(Suppl. 1):S423;Atkin et al. Diabetologia 2011;54(Suppl. 1):S53; Meneghini et al. Diabetes 2011;60(Suppl. 1A):LB10

IDeg Flexible OD (n=230)IDeg Fixed OD (n=226)IGlar OD (n=229)

IDeg Flexible: 0.63 events/PYEIDeg Fixed: 0.56 events/PYEIGlar: 0.75 events/PYE


Insulin degludec is available in two strengths, what you see is what you get

The insulin degludec U200 pen:•Ability to deliver up to 160U in one injection•No dose conversion if transferring from U100 (what you see is what you get)•Provides a 50% lower injection volume for patients requiring higher insulin doses

U100 penUp to 80U in 1U

increments

U200 penUp to 160U in 2U

increments

Tresiba® SmPC, Novo Nordisk, January 2013


UK NHS spend on basal insulins during 2012 (IMS data)1

• Only 8.3% of the basal insulin spend nationally is on human NPH insulin1

• If all prescriptions dispensed for analogue insulin between 2000 and 2009 had used a human insulin alternative, the NHS would have saved an estimated £625 million2

NPH=neutral protamine Hagedorn1.DATA ON FILE: UK NHS spend on basal insulins during 2012 2.Holden SE et al (2011) BMJ Open 1: e000258 )


Not Discussed

First choice gliptin – sitagliptinFirst choice GLP-1 – LixisenatideUse of GLP-1 therapy with basal insulin therapy

uk/tb/0213/0017a february 2013 new treatment options dr craig parkinson

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