uk/tb/0213/0017a february 2013 new treatment options dr craig parkinson
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UK/TB/0213/0017a February 2013
New treatment options
Dr Craig Parkinson
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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)
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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)
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
Tresiba® – A new basal insulin for adult patients with type 1
and type 2 diabetes
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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
IDeg OD (n=766)IGlar OD (n=257)
18% lower rate with IDeg (ns)
Time (weeks)
IDeg: 1.52 events/PYEIGlar: 1.85 events/PYE
UK/TB/0213/0017a February 2013
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)
IDeg: 0.25 events/PYEIGlar: 0.39 events/PYE
IDeg OD (n=766)IGlar OD (n=257)
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
Basal–bolus in T2D: confirmed hypoglycaemiaBEGIN® BB T2D
IDeg OD + IAsp (n=753)IGlar OD + IAsp (n=251)
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)
IDeg: 11.09 events/PYEIGlar: 13.63 events/PYE
UK/TB/0213/0017a February 2013
Basal–bolus in T2D: confirmed nocturnal hypoglycaemiaBEGIN® BB T2D
IDeg OD + IAsp (n=753)IGlar OD + IAsp (n=251)
SAS; LOCFComparisons: estimates adjusted for multiple covariatesGarber et al. Lancet 2012; 379:1498–507
25% lower rate with
IDeg, p=0.0399
Time (weeks)
IDeg: 1.39 events/PYEIGlar: 1.84 events/PYE
UK/TB/0213/0017a February 2013
Based on the long duration of action and flat profile insulin degludec can be administered at any time of the day
UK/TB/0213/0017a February 2013
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
UK/TB/0213/0017a February 2013
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/TB/0213/0017a February 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 )
UK/TB/0213/0017a February 2013
Not Discussed
First choice gliptin – sitagliptinFirst choice GLP-1 – LixisenatideUse of GLP-1 therapy with basal insulin therapy
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