UK/TB/0213/0017a February 2013
New treatment options
Dr Craig Parkinson
UK/TB/0213/0017a February 2013
Normal renal glucose handling1–3
Majority of glucose is
reabsorbed by SGLT2
(90%)
Proximal tubule
SGLT2
Remaining glucose
is reabsorbed by
SGLT1 (10%)
Glucose
Glucose
filtration
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.
Minimal to no
glucose excretion
UK/TB/0213/0017a February 2013
Dapagliflozin: A novel insulinindependent approach to remove excess
SGLT2
glucose
Dapagliflozin
Proximal tubule
Dapagliflozin
SGLT2
Glucose
filtration
Glucose
Increased
urinary
glucose
excretion
Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule1
1. FORXIGA Summary of Product Characteristics
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, 2011
4. FORXIGA Summary of Product Characteristics
UK/TB/0213/0017a February 2013
Dapagliflozin:
Reductions in HbA1c were sustained over 102 weeks
Placebo + metformin
(Mean baseline HbA1c 8.11% [65
mmol/mol])
0.2 (n=133)
0.0 (n=132)
+0.02%
(0.2
mmol/mol)
(95% Cl,
–0.20 to 0.23%;
n=28)
–0.2
0.80%
Dapagliflozin 10 mg + metformin (8.8
(Mean baseline HbA1c 7.92% [63
mmol/mol)
–0.4
mmol/mol])
–0.6
–5
difference
–0.78%
–0.8
(–8.5
mmol/mol)
–1.0
(95% Cl,
–0.97 to –0.60%;
n=57)
–1.2
0
0
8
16
24
37
50
63
76
Study week
89
102
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.
–10
HbA1c (mmol/mol)
mean change from baseline
HbA1c (%)
mean change from baseline
Primary endpoint
UK/TB/0213/0017a February 2013
Dapagliflozin: secondary benefit of weight loss over
102 weeks
Adjusted mean change
from baseline body weight (kg)
24 weeks (LOCF analysis)1
•
•
Dapagliflozin 10 mg
Placebo
+ metformin
+ metformin
102 weeks (repeated measures
2
Dapagliflozin 10analysis)
mg
Placebo
+ metformin
+ metformin
+1.36 kg
(n=73)
95% Cl
(0.53 to 2.20)
–2.9 kg
(n=133)
–0.9 kg
(n=136) 95%CI
-1.4 to -0.4
95% CI
(-3.3 to -2.4)
–1.70 kg
(n=95)
95% Cl
(-2.48 to 0.91)
3.1 kg
difference
p value not
calculated
2.0 kg
difference
p<0.0001
Adapted from Bailey CJ, et al. (2010) & Bailey CJ, et al. (2011)
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 #
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.
UK/TB/0213/0017a February 2013
Reductions in HbA1c with insulin +
dapagliflozin compared with insulin +
placebo at 24 weeks
Placebo +
insulin
–0.39%
(–4.3 mmol/mol)
-0.2
(n=193)
-0.4
-0.6
-0.8
0
-5
–0.96%
(–10.5 mmol/mol)
(n=194)
-1.0
0.57% (6.2
mmol/mol)
difference
-10
Adjusted mean change from
baseline HbA1c (mmol/mol)
Adjusted mean change from
baseline HbA 1c (%)
0.0
Dapagliflozin 10
mg + insulin
(95% CI, –0.72 to –
0.42%)
Adapted from Wilding J, et al. 2012
p<0.001
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. Wilding J, et al. Ann Intern Med 2012;156:405–415.
2. FORXIGA™. Summary of product characteristics.
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 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
Dapagliflozi
n
1. Wilding JPH et al. Ann Intern Med 2012;156:405–415.
2. FORXIGA™. Summary of product characteristics..
190
UK/TB/0213/0017a February 2013
Dapagliflozin: Consistent reduction in HbA1c at Week
24 across studies
Mean change in HbA1c(%)
Monotherapy1
Add-on to metformin2
Add-on to insulin4
Dapagliflozin (10
mg)
Placebo
–0.13
–0.23
(-3 mmol/mol)
Add-on to a
SU3
–0.30
(-1 mmol/mol)
–0.39
(-3 mmol/mol)
(-4 mmol/mol)
–0.89*
(-10 mmol/mol)
–0.84*
(-9 mmol/mol)
–0.82*
(-9 mmol/mol)
–0.96*
(-10 mmol/mol)
p<0.0001
p<0.0001
p<0.001
Baseline HbA1c:
Baseline HbA1c:
8.11%;
8.53%; 70 mmol/mol
65 mmol/mol
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.
Baseline HbA1c:
7.91%; 63 mmol/mol
1.
2.
3.
4.
Baseline HbA1c:
8.05%; 64 mmol/mol
p<0.0001
Ferrannini E et al. Diabetes Care 2010;33:2217–2224.
Bailey CJ et al. Lancet 2010;375:2223–2233.
Strojek K et al. Diabetes Obes Metab 2011;13:928–938.
Wilding JPH et al. Ann Intern Med 2012;156:405–415.
UK/TB/0213/0017a February 2013
NICE TA288
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.
http://publications.nice.org.uk/dapagliflozin-incombination-therapy-for-treating-type-2-diabetesta288
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
IDeg 0.8 U/kg
IGlar 0.8 U/kg
*
Insulin degludec
Half-life (hours)
Mean half-life
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
25.9
27.0
23.9
11.8
14.0
11.9
25.4
*Insulin glargine was undectable after 48 hours
Results from patients with type 1 diabetes
IDeg, insulin degludec; IGlar, insulin glargine
Heise et al. Diabetologia 2011;54(Suppl. 1):S425
12.5
UK/TB/0213/0017a February 2013
Insulin-naïve T2D: HbA1c and FPG over time
BEGIN® ONCE LONG
IDeg OD (n=773)
IGlar OD (n=257)
75
70
65
55
50
Treatment difference:
45
non-inferior
40
HbA1c (mmol/mol)
60
Treatment difference:
–0.43 mmol/L, p<0.05
35
0
0.0
26
Time (weeks)
Mean±SEM; full analysis set (FAS); last observation carried forward (LOCF)
Comparisons: estimates adjusted for multiple covariates
Zinman et al. Diabetes Care 2012;35:2464–71
0.0
26
Time (weeks)
UK/TB/0213/0017a February 2013
Insulin-naïve T2D: confirmed hypoglycaemia
BEGIN® ONCE LONG
IDeg OD (n=766)
IGlar OD (n=257)
18% lower
rate with
IDeg (ns)
IDeg: 1.52 events/PYE
IGlar: 1.85 events/PYE
Time (weeks)
Severe hypoglycaemia: IDeg, 0.00 events/PYE; IGlar, 0.02 events/PYE
SAS; LOCF; Comparisons: estimates adjusted for multiple covariates
PYE, patient-years of exposure
Zinman et al. Diabetes Care 2012; 35:2464–71
UK/TB/0213/0017a February 2013
Insulin-naïve T2D: nocturnal confirmed
hypoglycaemia
BEGIN®
IDeg OD (n=766)
IGlar OD (n=257)
ONCE LONG
36% lower
rate with
IDeg,
p<0.05
IDeg: 0.25 events/PYE
IGlar: 0.39 events/PYE
Time (weeks)
SAS; LOCF
Comparisons: estimates adjusted for multiple covariates
Zinman et al. Diabetes Care 2012; 35:2464–71
UK/TB/0213/0017a February 2013
Basal–bolus in T2D: HbA1c and FPG over
time
IDeg OD + IAsp (n=744)
BEGIN® BB T2D
IGlar OD + IAsp (n=248)
75
70
Treatment difference:
–0.29 mmol/L (ns)
65
60
55
50
45
40
HbA1c (mmol/mol)
Treatment difference:
non-inferior
35
0.0
0
26
Time (weeks)
Mean±SEM; FAS; LOCF; IAsp, insulin aspart
Comparisons: estimates adjusted for multiple covariates
Garber et al. Lancet 2012;379:1498–507
0.0
26
Time (weeks)
UK/TB/0213/0017a February 2013
Basal–bolus in T2D: confirmed
hypoglycaemia
IDeg OD + IAsp (n=753)
BEGIN® BB T2D
IGlar OD + IAsp (n=251)
18% lower
rate with
IDeg,
p=0.0359
IDeg: 11.09 events/PYE
IGlar: 13.63 events/PYE
Time (weeks)
Severe hypoglycaemia: IDeg, 0.06 events/PYE; IGlar, 0.05 events/PYE
SAS; LOCF; Comparisons: estimates adjusted for multiple covariates
Garber et al. Lancet 2012;379:1498–507
UK/TB/0213/0017a February 2013
Basal–bolus in T2D: confirmed nocturnal
hypoglycaemia
IDeg OD + IAsp (n=753)
BEGIN® BB T2D
IGlar OD + IAsp (n=251)
25% lower
rate with
IDeg,
p=0.0399
IDeg: 1.39 events/PYE
IGlar: 1.84 events/PYE
Time (weeks)
SAS; LOCF
Comparisons: estimates adjusted for multiple covariates
Garber et al. Lancet 2012; 379:1498–507
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 hypoglycaemia
IDeg Flexible OD (n=230)
BEGIN® FLEX T2D
IDeg Fixed OD (n=226)
IGlar OD (n=229)
23% lower rate with
IDeg Flexible than with
IGlar (ns)
18% higher rate with
IDeg Flexible than
with IDeg Fixed (ns)
IDeg Flexible: 0.63 events/PYE
IDeg Fixed: 0.56 events/PYE
IGlar: 0.75 events/PYE
SAS; LOCF
Comparisons: estimates adjusted for multiple covariates
Birkeland 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
UK/TB/0213/0017a February 2013
Insulin degludec is available in two
strengths, what you see is what you get
U100 pen
Up to 80U in 1U
increments
U200 pen
Up to 160U in 2U
increments
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
Tresiba®
SmPC, Novo Nordisk, January 2013
UK/TB/0213/0017a February 2013
UK NHS spend on basal insulins during 2012
(IMS data)1
NHS spend during 2012
Insulin glargine
£96,201,765
Insulin detemir
£52,157,155
Sub-total for basal insulin analogues £148,358,920
All human NPH insulins
£13,473,090
• 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 Hagedorn
1. 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 – sitagliptin
First choice GLP-1 – Lixisenatide
Use of GLP-1 therapy with basal insulin therapy