Transcript Insulin glargine

Advances in the treatment of Type 2 Diabetes
The role of insulin glargine
Insulin glargine, marketed by Sanofi-Aventis under the
name Lantus, is a long-acting basal insulin analogue, given
once daily to help control the blood sugar level of those with
diabetes. It consists of microcrystals that slowly release
insulin, giving a long duration of action of 18 to 26 hours, with
a "peakless" profile (according to the Lantus package insert).
Pharmacokinetically, it resembles basal insulin secretion of
non-diabetic pancreatic beta cells. Sometimes, in type 2
diabetes and in combination with a short acting sulfonylurea
(drugs which stimulate the pancreas to make more insulin), it
can offer moderate control of serum glucose levels. In the
absence of endogenous insulin—Type 1 diabetes, depleted
type two (in some cases) or latent autoimmune diabetes of
adults in late stage—Lantus needs the support of fast acting
insulin taken with food to reduce the effect of prandially
derived glucose.
Benefit
When standard NPH is administered at night, its peak of action can coincide
with the lower serum glucose levels associated with nocturnal metabolism
potentially setting the stage for nocturnal hypoglycaemia. Lantus is associated
with a lower risk of nocturnal hypoglycaemia.
Pharmacological specifications
Mechanism of action (pharmacodynamics)
Insulin glargine have substitution of glycine for asparagine at A21 and two
arginines added to the carboxy terminal of B chain. The arginine amino acids
shift the isoelectric point from a pH of 5.4 to 6.7, making the molecule more
soluble at an acidic pH, allowing for the subcutaneous injection of a clear
solution. The asparagine substitution prevents deamidization of the acidsensitive glycine at acidic pH. In the neutral subcutaneous space, higher-order
aggregates form, resulting in a slow, peakless dissolution and absorption of
insulin from the site of injection. It can achieve a peakless level for at least 24
hours.
Acceptance and repartition in the body (pharmacokinetic)
Lantus is formulated at an acidic pH 4, where it is completely water soluble.
After subcutaneous injection of the acidic solute (which can cause discomfort
and a stinging sensation), when a physiologic pH (approximately 7.4) is
achieved the increase in pH causes the insulin to come out of solution
resulting in the formation of higher order aggregates of insulin hexamers. The
higher order aggregation slows the dissociation of the hexamers into insulin
monomers, the functional and physiologically active unit of insulin. This
gradual process ensures that small amounts of Lantus are released into the
body continuously, giving an almost peakless profile.
Usage
Mixing with other insulin preparations
Unlike some other longer-acting insulins, Lantus must not be diluted or
mixed with other insulin or solution in the same syringe However, this
restriction has been successfully challenged in trials conducted by Kaplan,
Rodriguez, Smith, Haymond, and Heptulla of Texas Childrens Hospital
Other information
Development
The development of Lantus was conducted at Sanofi-Aventis's
biotechnology competence center in Frankfurt-Höchst. Sanofi supplies the
product to over 100 countries and more than 3,5 million patients
worldwide. This makes Lantus Germany's largest and most important
export pharmaceutical product. Sanofi-Aventis increased its turn-over with
Lantus around 28% to 2,45 Billion €, therefrom 130 Million € in Germany,
where approx. 1,8 Mio. people with diabetes applied this preparation. In
2007 Lantus ranked place 15 on top-selling pharmaceutical products in
Germany.
The investment in the production of Lantus and insulin-pen-manufacturing
at the location Frankfurt-Höchst lied at 700 Mio. €. In 2008 a new
manufacturing plant was established for further insulin-pen with an
investment sum of 150 Mio. €. At Sanofi-Aventis the production of Lantus
created 3000 jobs in Berlin and Frankfurt-Höchst.
On June 9, 2000 the European Commission approbated Sanofi-Aventis
Germany Ltd. the launching of Lantus in the entire European Union. The
admission was prolonged on June 9, 2005
Advantages
International clinical studies have confirmed the advantages
of insulin glargine in the treatment of heavy hypoglycaemia
compared to standard NPH insulin. Insulin glargine reduces
the risk of severe nocturnal hypoglycaemia. Extensive clinical
studies (ACCORD) have confirmed the higher risk of mortality
with higher incidence of severe hypoglycaemia. A comparison
trial of insulin detemir and glargine proved that subjects
randomized to detemir used slightly higher daily insulin
doses, but gained less weight on average than glarginetreated subjects. Other systematic reviews corroborate the
results of benefit of insulin glargine regarding lower incidence
of severe hypoglycaemia.
On June 13, 2009, Diabetologia, the journal of European
Association for the Study of Diabetes (EASD), published the
results of a 5 year long-term observational, retrospective
analysis. During the study no other safety issues, such as
unexpected adverse events for either insulin emerged.
However, insulin glargine was associated with a lower
incidence of severe hypoglycaemia compared with NPH
insulin.
Possible cancer link
On June 26, 2009, Diabetologia published the results of four large-scale
registry studies from Sweden, Germany, Scotland and the rest of the UK.
The German study, of around 127,000 insulin-treated patients from an
insurance database, suggested a possible link between insulin glargine
(Lantus) and increased risk of developing cancer. The risk of cancer was
dose-dependent, with those taking higher doses of Lantus apparently at
increased risk. Whilst the authors stressed the limitations of the study and
recommended that patients prescribed Lantus continue to take the drug,
the results led to the EASD making "an urgent call for more research into a
possible link between use of insulin glargine (an insulin analogue, brand
name Lantus) and increased risk of cancer.
The European Medicines Agency (EMEA) responded, stating that the
results of the four studies were inconsistent, and that a relationship
between insulin glargine and cancer could neither be confirmed nor
excluded. They announced that they would undertake further detailed
assessment of the studies’ results and any other relevant information,
including several potential confounding factors that had not been fully
taken into account by the studies. Patients being treated with insulin
glargine were advised to continue their treatment as normal. The following
month, the EMEA reported back, concluding that "the available data does
not provide a cause for concern and that changes to the prescribing advice
are therefore not necessary.
The American Diabetes Association (ADA) also responded to the
Diabetologia report, describing the published registry studies as “conflicting
and confusing” and “inconclusive”. They advised patients against
discontinuing Lantus and warned against "over-reaction.
New study confirms cancer link
Type 1 diabetics who used Lantus had a 2.9-fold greater
chance of cancer, while those who took the generic drug
metformin had an 8 percent lower risk, according to a study
presented on 9 December 2011 at the San Antonio Breast
Cancer Symposium. Researchers examined medical records of
23,266 patients in southern Sweden.
The researchers were unable to identify which types of cancer
were most common among Lantus users, said Hakan Olsson,
lead researcher and professor of oncology at Lund University.
They plan to follow the patients, and investigate different forms
of treatment for Type 1 diabetes, including Novo Nordisk A/S’s
long- acting insulin Levemir, to tease out any differences, he
said.
“Women should be aware that diabetes and breast cancer may
be related,” Olsson said in a telephone interview. “The diabetes
itself could play a role in the development of cancer and now
data is emerging that drug therapy may also be important in
relation to cancer.
Insulin glargine amino acid sequence
A chain
1
Gly
2
Ile
Asn
Deletion
10 11 12 13 14 15 16 17 18 19 20 21
Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Gly
Addition
S
S
3
4
5
6
7
8
9
Val Glu Gln Cys Cys Thr Ser
S
B chain
S
S
S
Addition
Addition
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro Lys Thr Arg Arg

Asparagine at position A21 replaced by glycine
– Provides stability

Addition of two arginines at the C-terminus of the B chain
– Soluble at slightly acidic pH
LANTUS® (insulin glargine) EMEA Summary of Product Characteristics 2006.
Lantus®

Insulin glargine is the first basal insulin analogue

Its extensive clinical development program shows that once-daily insulin
glargine consistently allows HbA1c levels to be reduced to <7% in patients
with T1DM or T2DM1–6

Evidence from randomized and ‘real life’ studies show that glycemic control
is achieved with:
 Reduced incidence of hypoglycemia compared with NPH3,7,8 or premix 70/309 insulins
 Smaller insulin dose (-77%) than detemir16
 A minimal impact on weight10–14

The clinical benefits of insulin glargine are attributed to its peakless,
prolonged action profile that closely mimics endogenous insulin secretion
and results in 24 hours of activity1
1. Porcellati F et al. Diabet Med 2004;21:1213–1220
2. Gerstein H et al. Diabet Med 2006;23:736–742
3. Riddle M et al. Diabetes Care 2003;26:3080–3086
4. Bretzel RG et al. Diabetes 2006;55(suppl). Abstract 326–OR
5. Yki-Jarvinen H et al. Diabetes Care 2007;30:1364–1369
6. Bergenstal R et al. Diabetes 2006;55(suppl). Abstract 441–P
7. Rosenstock J et al. Diabetes Care 2005;28:950–955
8. Mullins P et al. Clin Ther 2007;29:1607–1619
9. Janka H et al. Diabetes Care 2005;28:254–259
10. Schreiber S et al. Diabetes Obesity Metab 2007;9:31–38
11. Yki-Jarvinen H et al. Diabetes Care 2000;23:1130–1136
12. Fritsche A et al. Ann Int Med 2003;138:952–959
13. Yki-Jarvinen H et al. Diabetologia 2006;49:442–451
14. Rosenstock J et al. Diabetes Care 2006;29:554–559
15. Lepore M et al. Diabetes 2000;49:2142–2148
16. Rosenstock J et al. Diabetologia 2008;51:408–416
Lantus®

These pharmacodynamic properties are clinically translated into:
 Once-daily administration1
 Effective lowering of FBG and PPBG over 24 hours when compared with NPH2 and
premix 70/303 insulins

Insulin glargine can be injected once a day either in the morning or
at bedtime without affecting glucose control4

Insulin glargine is easy to titrate thanks to simple titration algorithms5, 6 that
facilitate patients’ contribution to the management of their diabetes6

These features allow efficient and safe initiation of insulin therapy
in patients with T2DM uncontrolled on OHAs5, 7, 3
1. Lantus Prescribing Information
2. Yki-Jarvinen H et al. Diabetes Care 2000;23:1130–1136
3. Janka H et al. Diabetes Care 2005;28:254–259
4. Standl E et al. Hormone Metab Res 2006;38:172–177
5. Gerstein HC et al. Diabet Med 2006;23:736–742
6. Davies M et al. Diabetes Care 2005; 28:1282–1288
7. Riddle M et al. Diabetes Care 2003;26:3080–3086

Peakless profile1

Long duration of action1

Flexible dosing

Simple titration

Suitable for treat-to-target
schedules
Insulin level
Properties of the ideal basal insulin
0
4
8
12
16
Hours post dose
1. Rosenstock J. Clin Cornerstone 2001;4:50–64.
20
24
Basal insulin analogues offer advantages over basal human
insulins

Compared with human basal insulins, basal insulin analogues:




Have more physiological action profiles
Exhibit less variability
Reduce the risk of hypoglycaemia
Are associated with less weight gain
Insulin level
Human insulin (intermediate acting)
Insulin level
Insulin analogue (long acting)
0
4
8
12
16
20
24
Hours post dose
Adapted from Tibaldi J, and Rakel R, Int J Clin Pract 2007;61:633–44.
Adapted from Choe C, et al. J Natl Med Assoc 2007;99:357–67.
0
4
8
12
16
Hours post dose
20
24
Don’t Forget
Insulin Glargine

Better Control

Less Hypoglycemia

Less Weight Gain

Only One Shot a day.
Types of basal insulin
Intermediate-Acting
(e.g. NPH, lente)
Long-Acting
(e.g. ultralente)
Long-Acting Analogues
(glargine, detemir)
Onset
1-3 hr(s)
3-4 hrs
1.5-3 hrs
Peak
5-8 hrs
8-15 hrs
No peak with glargine,
dose-dependent peak with
detemir
Up to 18 hrs
22-26 hrs
9-24 hrs (detemir);
20-24 hrs (glargine)
Duration
Rossetti P, et al. Arch Physiol Biochem 2008;114(1): 3 – 10.
Advantages of insulin therapy

Oldest medication, with most clinical experience

Most effective in lowering glycemia
 Can decrease any level of elevated HbA1c
 No maximum dose of insulin

Beneficial effects on triglyceride and HDL-c
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Disadvantages of insulin therapy

Weight gain ~ 2-4 kg
 ± proportional to the correction of glycemia
 Predominantly the result of  glycosuria

Hypoglycemia
 Rates of severe hypoglycemia in patients with T2DM are low in
treat-to-target clinical trials (compared to T1DM):
-
Type 1 DM: 61 events per 100 patient-years
Type 2 DM: 1 to 3 events per 100 patient-years
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Titrate basal insulin as long as FPG above
target range
INITIATE
• Bedtime or morning long-acting insulin OR
• Bedtime intermediate-acting insulin
Daily dose: 10 units or 0.2 units/kg
Check
FPG
daily
• Increase dose by 2 units every 3 days
TITRATE
MONITOR
until FPG is 3.89–7.22 mmol/L
(70–130 mg/dL)
• If FPG is >10 mmol/L (>180 mg/dL),
increase dose by 4 units every 3 days
Continue regimen and
check HbA1c every 3 months
FPG, fasting plasma glucose
Nathan DM, et al. Diabetes Care 2009;32:193-203.
In the event of hypoglycemia or
FPG level <3.89 mmol/L
(<70 mg/dL)
• Reduce bedtime insulin dose
by 4 units, or by 10% if >60
units
Insulin glargine: the first long-acting insulin analogue
The mechanics of sustained release1,2
The mechanics of sustained release1,2
Injection of an acidic solution
(pH 4.0)3

Microprecipitation of insulin glargine
in subcutaneous tissue (pH 7.4)3

Slow dissolution of free insulin
glargine hexamers from
microprecipitates (stabilized
aggregates)3

Protracted action3
1. Bell DSH. Drugs 2007;67:1813–1827
2. McKeage K et al. Drugs 2001;61:1599–1624
3. Kramer W. Exp Clin Endocrinol Diabetes 1999;107(suppl 2):S52–S61
The 24-hour peakless action profile of insulin
glargine allows once-daily injection
NPH
Ultralente
Glucose infusion rate (mg/kg/min)
sc
injection
0.3 IU/kg
or CSII
0.3 IU/kg/
24/h
CSII
Lispro
Flat action
profile lasting
for 24 hours
Glargine
0
4
8
12
16
20
Time (hours)
Rates of glucose infusion needed to maintain plasma glucose
at 130 mg/dL [7.2 mmol/L] after sc injection in patients with T1DM (n=20)
1. Lepore M et al. Diabetes 2000;49:2142–2148
24
Basal insulin analogues
T1DM patients (n=24)2
SC injection
0.35 IU/kg
24
20
3
16
12
2
8
Insulin glargine
1
4
Insulin detemir
0
0
0
4
8
12
Time (hours)
2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.
16
20
24
Glucose infusion rate (µmol/kg/min)
Glucose infusion rate (µmol/kg/min)
Glucose infusion rate (mmol/kg/min)
4
HbA1c is reduced ≤7% with once-daily insulin glargine
T1DM
T2DM
Basal-Bolus
Insulin glargine + OHAs
HbA1c (%)
Basal-Bolus
2
1
4
5
3
12 months
(n=61)
p<0.05 vs. NPH
24 weeks
(n=206)
p=0.0007 vs.
conventional therapy
1. Porcellati F et al. Diabet Med 2004;21:1213–1220
2. Gerstein H et al. Diabet Med 2006;23:736–742
3. Riddle M et al. Diabetes Care 2003;26:3080–3086
24 weeks
(n=367)
p=ns vs. NPH
6
44 weeks
(n=174)
p=ns vs.
3xlispro
24 weeks
(n=58 group
education arm)
24 weeks
(n=137 carb
counting arm)
4. Bretzel RG et al. Diabetes 2006;55(suppl). Abstract 326–OR
5. Yki-Jarvinen H et al. Diabetes Care 2007;30:1364–1369
6. Bergenstal R et al. Diabetes 2006;55(suppl). Abstract 441–P
Significantly more patients reach HbA1c target
without nocturnal hypoglycemia with insulin glargine
p<0.05
Final dose:
Glargine
47 IU
NPH
42 IU
Glargine
Patients (%)
Mean HbA1c (%)
NPH
Target HbA1c %
0
4
8
12
Weeks
16
20
24
HbA1c ≤7% without
documented nocturnal hypoglycemia
24-week study comparing bedtime once-daily glargine or
NPH in addition to OHAs in 756 insulin-naϊve patients with T2DM
1. Riddle M et al. Diabetes Care 2003;26:3080–3086
Insulin glargine consistently reduces hypoglycemia in
T2DM vs. NPH
RR=11%, p=0.0006
RR=46%, p=0.0442
RR=59%, p=0.0231
Glargine
Patients with hypoglycemia (%)
NPH
Overall
hypoglycemia
Severe
hypoglycemia
Severe nocturnal
hypoglycemia
Meta-analysis of four randomized studies comparing insulin
glargine to once-or twice-daily NPH in 2,304 patients with T2DM
1. Rosenstock J et al. Diabetes Care 2005;28:950−955
For any level of HbA1c, hypoglycemic event rates
are lower with insulin glargine than NPH in T1DM
Hypoglycemic events per 100 patient-years
Glargine
NPH
p-value (between
Treatments): 0.004
6
7
8
LOCF HbA1c %
9
10
Associations between end of study HbA1c levels and rates of hypoglycemia during treatment with NPH or glargine in five
studies in 1,899 patients. Curves derived from a negative binomial regression model, with adjustments for covariates
1. Mullins P et al. Clin Ther 2007;29:1607–1619
For any HbA1c level, hypoglycemic event rates
are lower with insulin glargine than NPH in T2DM
Hypoglycemic events per 100 patient-years
Glargine
NPH
p-value (between
Treatments): 0.021
6
7
8
9
10
LOCF HbA1c %
Associations between end of study HbA1c levels and rates of hypoglycemia during treatment with NPH or insulin
glargine in six studies involving 3,175 patients with T2DM. Curves derived from a negative binomial regression model,
with adjustments for covariates
1. Mullins P et al. Clin Ther 2007;29:1607–1619
Similar effect on weight as comparators in clinical studies
Glargine bedtime
Glargine morning
Premix
Rosiglitazone
NPH
ns
Mean weight gain (kg)
p=0.02
Yki-Jarvinen1 Treat-to-Target2
Fritsche3
LANMET4
LAPTOP5
1. Yki-Jarvinen H et al. Diabetes Care 2000;23:1130–1136. 2. Riddle M et al. Diabetes Care 2003;26:3080–3086.
3. Fritsche A et al. Ann Int Med 2003;138:952–959. 4. Yki-Jarvinen H et al. Diabetologia 2006;49:442−451.
5. Janka H et al. Diabetes Care 2005;28:254–259. 6. Rosenstock J et al. Diabetes Care 2006;29:554–559
Triple
Therapy6
Insulin glargine provided better glycaemic control
with fewer hypoglycemia than premix in elderly
patients
Sub-population of patients aged ≥65 years (n=130)
HbA1c
Hypoglycaemia
Premixed human insulin 30/70 BID
0
–0.5
–1.0
–1.5
–1.4
p=0.003
–2.0
9.1
10
–1.9
Insulin glargine was well titrated
and more effective
Janka H, et al. J Am Geriatr Soc 2007;55:182−8.
Incidence
(episodes/patient-year)
Change from baseline (%)
Insulin glargine
8
p<0.008
6
4
3.7
2
0
Insulin glargine was associated
with fewer hypos
Once-daily insulin glargine can be administered
in the morning or at bedtime
“Flexibility of injection time should facilitate the initiation of insulin treatment
and adherence to the insulin regimen in patients with T2DM”
Patients achieving HbA1c ≤7%
Proportion of patients (%)
Proportion of patients (%)
Frequency of nocturnal hypoglycemia
Morning
Bedtime
24-week, randomized study comparing evening to morning insulin glargine
injection in 624 patients with T2DM poorly controlled on OHAs
No difference between morning and bedtime treatment arms
1. Standl E et al. Hormone Metab Res 2006;38:172–177
Basal, prandial and premixed insulin have
different action profiles
Premixed insulin
Reduces fasting
hyperglycaemia
Reduces postprandial
hyperglycaemia
Reduces fasting and
postprandial hyperglycaemia
Long duration
of action
Short duration
of action
Long biphasic
duration of action
Inject morning and/or
evening
Inject at mealtimes
Inject at mealtimes
Insulin level
0
4
8 12 16 20 24
Hours post dose
Insulin level
Prandial insulin
Insulin level
Basal insulin
0
4
8 12 16 20 24
Hours post dose
1. Rave K, et al. Diabetes Care 2006;29:1812–7.
2. Becker RHA, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43.
0
4
8 12 16 20 24
Hours post dose
LAPTOP study: Comparison of insulin glargine added
to an OHA regimen versus switching to premixed
insulin
Patients with T2DM
HbA1c: 7.5% to 10.5%
and FBG: ≥6.7 mmol/L
(≥120 mg/dL) and
treated with OHAs
(n = 364)
Screening
Run-in phase
3–14 weeks
R
A
N
D
O
M
I
S
A
T
I
O
N
Insulin glargine + OHAs (n = 177)
Initial dose: 10 IU once daily in
the morning
Human premixed insulin (70/30) (n
= 187)
Initial dose: 10 IU before
breakfast and 10 IU before dinner
Treatment phase
24 weeks
Subjects taking sulphonylurea and metformin for at least a month were enrolled. Sulphonylurea was
replaced with 3 or 4 mg glimepiride during run-in phase. OHA dose remained the same throughout the
study in the insulin glargine arm, while OHAs were discontinued in the premixed insulin arm.
Janka H, et al. Diabetes Care 2005;28:254–9.
Significantly greater reduction in FBG and
PPBG with insulin glargine vs premix
14
Premixed insulin twice daily
Insulin glargine + OHAs
Baseline
12
10
*
Blood glucose (mmol/L)
16
8
6
4
*
*
*
Endpoint
Fasting After
Lunch
breakfast
After
lunch
Dinner
*
After Bedtime 03.00
dinner
Time of day
*p < 0.05 for treatment comparison of
changes from baseline to endpoint
Janka H, et al. Diabetes Care 2005;28:254–9.
Insulin glargine provided better glycaemic
control and less weight gain than premix
Insulin
glargine‡
0
2.1
-0.5
-1.0
-1.5
-2.0
†Twice
Final daily dose:
Premixed insulin 64.5 IU
Insulin glargine 28.2 IU
2.5
Weight gain (kg)
HbA1c change from baseline (%)
Premixed
insulin†
-1.31
-1.64
p = 0.0003
2.0
p = NS
1.4
1.5
1.0
0.5
0
Premixed
insulin†
Insulin
glargine‡
daily; ‡plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.
Events per patient per year
Lower incidence of hypoglycaemia with
insulin glargine versus premix
p < 0.0001
12
10
Premixed insulin
Insulin glargine*
9.87
8
p = 0.0009
5.73
6
4.07
4
2,62
2
p = 0.0449
1,04
0.51
0
All confirmed
hypoglycaemia
Confirmed
symptomatic
Confirmed
nocturnal
Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3 mmol/L)
*Plus OHAs
Janka H, et al. Diabetes Care 2005;28:254–9.
Detemir vs. glargine in T2DM: same clinical outcomes but detemir
at a higher daily dose and bid in most patients



Detemir is used bid in 55% of patients
Detemir mean daily dose is 77% higher than glargine dose
Higher drop-out with detemir (21%) than with glargine (13%)
HbA1c (%)
Final dose (U/kg):
Glargine od
0.44
Detemir od or bid
0.78
Glargine
Detemir
0.0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treatment time (weeks)
52-week, randomized, treat-to target trial comparing detemir to glargine when
administered as add-on to OHAs in 582 insulin naïve T2DM patients
1. Rosenstock J et al. Diabetologia 2008;51:408–416
+77%
Glargine and detemir are equally effective but detemir requires
higher doses and often two injections
1.00
0.78
Mean dose (U/kg)
0.75
0.50
0.44
0.25
0.00
Glargine
Detemir
Patients receiving 2 injections (%)
100
75
55
50
25
0
0
Glargine
Detemir
Rate of hypoglycemia was similar between
the two treatment arms
Rosenstock J, et al. Diabetologia. 2008;51(3):408-416.
A1C Complications
20
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
15
Relative Risk
13
11
9
7
5
3
1
6
7
8
9
10
11
12
A1C (%)
DCCT, Diabetes Control and Complications Trial.
1. Adapted from Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243-254.
2. DCCT. N Engl J Med. 1993;329:977-986.
3. DCCT. Diabetes. 1995;44:968-983.
Initial Insulin Delivery Device
Lantus SoloStar
What are the SoloStar components?
Lessons from UKPDS:
Better control in T2DM means fewer complications
1% reduction in HbA1c
Risk reduction*
Deaths from diabetes
-21%
Myocardial Infarction
-14%
Microvascular complications
-37%
1%
Peripheral vascular disorders
*p<0.0001 n=3,642 type 2 diabetes patients
1. Stratton IM et al. BMJ 2000;321:405–412
-43%
Change over time in guidelines
for evaluating hyperglycemia
Time period
<1993 (pre-DCCT)
>1993 (post-DCCT)
1997 to present
FBG
(mg/dL)
FPG
(mg/dL)
HbA1c
(%)
200
-
9-10
140
150
8
80-120
90-130
<7
New diagnostic
criteria for diabetes
-
126
-
Definition of
normoglycemia
99
109
<6
Type of guideline
Threshold for
initiating or changing
treatment
Threshold for
initiating or changing
treatment
Recommended
treatment goals
(UKPDS)
2000
FBG: fasting blood glucose
FPG: fasting plasma glucose
DCCT: Diabetes Control and Complications Trial
Hollander PA. Postgrad Med 2000;Special Report:4-10.
HbA1c targets in current guidelines
HbA1c target (%)
ADA/EASD
IDF
NICE
AACE
France
Canada
Australia
Latin America
<7.0
≤6.5
<6.5
≤6.5
<6.5*
≤7.0
≤7.0
<6.5
*If on single or double therapy; if on triple therapy or insulin, then HbA1c <7%
Nathan DM, et al. Diabetes Care 2009;32 193-203
http://www.idf.org/home/index.cfm?node=1457
http://www.nice.org.uk/nicemedia/pdf/CG66diabetesfullguideline.pdf
Endocrine Practice Vol 13 (Suppl 1) May/June 2007
Drouin P, et al. Diabetes & Metabolism (Paris) 1999;25:72-83.
Canadian Diabetes Association Canadian J Diab:32(suppl. 1):S1-201
http://www.nhmrc.gov.au/publications/synopses/_files/di10.pdf
http://www.revistaalad.com.ar/guias/GuiasALAD_DMTipo2_v3.pdf
Rationale for glycemic goals

Glycemic goals of therapy are based on:
 Clinical studies
-
Type 1: DCCT, Stockholm Diabetes Intervention Study
Type 2: UKPDS, Kumamoto
 Epidemiological data

"Normal" HbA1c
 Upper limit of nondiabetic range: 6.1%

Goals of therapy in DCCT and UKPDS
 Neither study was able to maintain HbA1c level
in the nondiabetic range
 HbA1c ~ 7% in intensive treatment groups
-
i.e., 4 SD above nondiabetic mean
DCCT Research Group. N.Eng.J.Med.1993;329:977-986.
Raichard P, et al. Acta Medica Sandinavica 224(2):115-122.
UKPDS Group Lancet 1998;352:837-53.
Ohkubo Y, et al. Diabetes Res Clin Pract 1995;28:103–117.
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Benefits of intensive vs conventional
glycemic management
10
DCCT conventional
HbA1c (%)
9
UKPDS conventional
8
UKPDS intensive
7
DCCT intensive
6
5
0
1
2
3
4
5
Time (y)
Turner R, et al. Ann Intern Med. 1996;124:136-145.
6
7
8
9
Risk of complications
Benefits of lowering hemoglobin HbA1c
Relative Risk
of complications
16
12
8
4
0
6
7
8
9
10
11
12
270
300
Hemoglobin HbA1c (%)
Average Glucose
mg/dl
120
150
Adapted from UKPDS 33: Lancet 1998;352:837-853.
Adapted from DCCT Study Group. N Engl J Med 1993;329:977.
180
210
240
Why guidelines for the treatment of T2DM?

Diabetes is a complex and progressive disease, requiring
timely treatment escalation

Guidelines interpret existing evidence in order to help
all physicians

The increase in the number of available therapies has
increased treatment options

Guidelines should be revised as new evidence accrues

Guidelines do not replace clinical judgement in
the individual patient
Nathan DM, et al. Diabetes Care 2009;32 193-203.
History of ADA/EASD consensus algorithm

First Consensus algorithm
 August 20061

1st Update
 January 2008: Update regarding thiazolidinediones2

2nd Update
 January 20093
1. Nathan DM, et al. Diabetes Care 2006;29(8):1963-72.
2. Nathan DM, et al. Diabetes Care 2008;31(1):173-5.
3. Nathan DM, et al. Diabetes Care 2009;32:193-203.
HbA1c targets should be individualized

Goal of therapy
 In general: HbA1c <7%
 In the individual patient: HbA1c as close to 6% as possible
without significant hypoglycemia

Call to action: HbA1c 7%

Less stringent goals may be appropriate for:
 Patients with a history of severe hypoglycemia
 Patients with limited life expectancies
 Very young children or older adults
 Individuals with co-morbid conditions
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Principles in selecting antihyperglycemic
interventions

Effectiveness in lowering blood glucose
 When high HbA1c (≥8.5%)
-

Classes with greater and more rapid glucose-lowering
effectiveness are recommended
Potentially earlier initiation of combination therapy
Extraglycemic effects that may reduce long-term
complications
 Hypertension, dyslipidemia, BMI, insulin resistance, insulin
secretory capacity



Safety profiles
Tolerability
Ease of use
Nathan DM, et al. Diabetes Care 2009;32 193-203.
ADA/EASD consensus algorithm
Overarching principles


Early intervention
Patient’s empowerment
 Education, SMBG, treatment adjustment



Shorten delays in treatment changes
Achieve and maintain normal glycemic goals
Add medications, transition to new regimens quickly
 Whenever HbA1c levels are ≥7%
STEP 1: Lifestyle intervention + metformin
STEP 2: Add another agent – basal insulin or SU
STEP 3: Intensify therapy
Timely basal insulin therapy for patients not meeting targets
SMBG: self-monitoring blood glucose
Nathan DM, et al. Diabetes Care 2009;32:193-203.
Expected HbA1c reduction according
to intervention
Intervention
Lifestyle interventions
Metformin
Sulfonylureas
Insulin
Glinides
Thiazolidinediones
-Glucosidase inhibitors
GLP-1 agonist
Pramlintide
DPP-IV inhibitors
1. Repaglinide is more effective than nateglinide
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
Expected ↓ in HbA1c (%)
1
1
1
1.5
1
0.5
0.5
0.5
0.5
0.5
to 2%
to 2%
to 2%
to 3.5%
to 1.5%1
to 1.4%
to 0.8%
to 1.0%
to 1.0%
to 0.8%
ADA/EASD consensus algorithm
Tier 1:
Call to action if HbA1c is 7%
well-validated therapies
Lifestyle + Metformin
+ Basal insulin
At diagnosis:
Lifestyle +
Metformin
STEP 1
Lifestyle + Metformin
+ Intensive insulin
Lifestyle + Metformin
+ Sulfonylurea
STEP 2
STEP 3
Tier 2:
Less well validated
therapies
Lifestyle + Metformin
+ Pioglitazone
No hypoglycaemia
Oedema/CHF
Bone loss
Lifestyle + metformin
+ GLP-1 agonist
No hypoglycaemia
Weight loss
Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Lifestyle + Metformin
+ Pioglitazone
+ Sulfonylurea
Lifestyle + metformin
+ Basal insulin
Traditional approaches for intensifying insulin
therapy: basal-bolus and premixed insulin
Lifestyle modification and OHAs
Basal
e.g. insulin glargine
Premixed insulin x1
Premixed insulin x2
Premixed insulin x3
Basal–bolus
e.g. insulin glargine + insulin glulisine x3
Hirsch I, et al. Clin Diabetes 2005;23:78−86.
New approaches for intensifying insulin
therapy: basal-plus
Lifestyle modification and OHAs
Basal
e.g. insulin glargine
Premixed insulin x1
Basal-plus
e.g. insulin glargine + insulin glulisine x1
Premixed insulin x2
Basal-plus
e.g. insulin glargine + insulin glulisine x2
Premixed insulin x3
Basal–bolus
e.g. insulin glargine + insulin glulisine x3
As per ADA/EASD guidelines
A logical stepwise approach
Basal bolus
Basal plus
Basal plus
Basal insulin
Basal +
2 prandial
Basal +
3 prandial
Basal +
1 prandial
once daily
(treat-to-target)
Lifestyle
+
Metformin
± SU
HbA1c ≥7.0%, FBG on target
PPG ≥160 mg/dL
HbA1c ≥7.0%
Time
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
ADA/EASD consensus algorithm
Tier 1: Well-validated therapies

These interventions represent the best established and most effective and costeffective therapeutic strategy for achieving the target glycemic goals
STEP 1
At diagnosis:
Lifestyle +
Metformin
STEP 2
STEP 3
Lifestyle + Metformin
+ Basal insulin
Lifestyle + Metformin
+ Intensive insulin
Lifestyle + Metformin
+ Sulfonylurea
When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness,
or potentially earlier initiation of combination therapy, are recommended
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Attributes of metformin
• Decreases hepatic glucose output
How it works
Expected HbA1c
reduction
• Lowers fasting glycemia
1 to 2% (monotherapy)
• GI side effects
Adverse events
• Lactic acidosis (extremely rare)
Weight effects
Weight stability or modest weight loss
CV effects
Demonstrated beneficial effect in UKPDS which needs
to be confirmed
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
Little benefit, if any, to go over 2000 mg
Fasting plasma glucose
HbA1c
Metformin Dose
Metformin Dose
mg
500 1000 1500 2000 2500
0.0
-1
-2
- 20
*
- 40
**
-3
†
- 60
-4
-5
†
- 80
Change vs. placebo (%)
0
(mg/dL)
Change vs. placebo (mmol/L)
500 1000 1500 2000 2500
-0.5
-1.0
-1.5
†
-2.0
†
†
†
-2.5
* p<0.05
** p<0.01
†
Garber AJ, Am J Med 1997;102:491-7.
†
p<0.001 vs placebo
†
mg
ADA/EASD consensus algorithm: step 2
STEP 2
STEP 1
Lifestyle
+ Metformin
+ Basal insulin
At diagnosis:
Lifestyle
+
Metformin
HbA1c 7%
Lifestyle
+ Metformin
+ Sulfonylurea
When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness,
or potentially earlier initiation of combination therapy, are recommended
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
ADA/EASD consensus algorithm: step 2

If step 1 fails to achieve or sustain HbA1c <7%, another
medication should be added within 2-3 months

The HbA1c level will determine (in part) which agent is
selected next:
 Most of newly diagnosed Type 2 Diabetic patients will usually
respond to sulfonylurea*
 Basal insulin if HbA1c >8.5% or symptoms of hyperglycemia
* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide
Nathan DM, et al. Diabetes Care 2009;32:193-203.
Attributes of sulfonylureas
How they work
Enhance insulin secretion
Expected HbA1c
reduction
1 to 2%
Adverse events
Hypoglycemia*
Weight effects
~ 2 kg weight gain common when therapy initiated
CV effects
None substantiated by UKPDS or ADVANCE study
(but severe episodes are infrequent)
* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than other
second- generation sulfonylureas (gliclazide, glimepiride, glipizide)
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
Adding sulfonylurea to metformin is
particularly effective in lowering HbA1c
Drug 1 more beneficial
Drug 1 less beneficial
Drug 1
Glyb vs. other SU
TZD vs. SU
TZD vs. Met
Repag vs. SU
SU vs. Met
SU vs. Acarbose
Met + TZD vs. Met
SU + TZD vs. SU
Met + SU vs. Met
Met + SU vs. SU
Glyb: glyburide
TZD: thiazolidinedione
Repag: repaglinide
SU: sulfonylurea
Met: metformin
Bolen S, et al. Ann Intern Med 2007;147:386-399.
-1.5
-1.0
-0.5
0
Weighted mean difference in
HbA1c Value, %
0.5
ADA/EASD consensus algorithm: step 2
Insulin initiation
STEP 2
STEP 1
At diagnosis:
Lifestyle
+
Metformin
HbA1c 7%
Lifestyle
+ Metformin
+ Basal insulin
HbA1c 7%
Lifestyle
+ Metformin
+ Sulfonylurea
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Attributes of insulin
How it works
Expected HbA1c
reduction
Direct compensation for lack of insulin sensitivity
• 1.5 to 3.5%
• No maximum dose +++
Adverse events
Hypoglycemia
Weight effects
Weight gain of ~ 2–4 kg
• Beneficial effect on TG and HDL
CV effects
• Weight gain may have an adverse effect on CV risks
HDL:
TG: triglycerides
CV: cardiovascular
Nathan DM, et al. Diabetes Care 2009;32:193-203.
History of Diabetes: milestones in diabetes
treatment
1920
1940
1960
NPH
insulin
Insulin
discovered
1980
A1C
2000
DCCT
Insulin
glargine
Metformin
First
sulphonylureas
Insulin
pump
Lente
insulins
UKPDS
Rapid-acting
insulin
DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom Prospective Diabetes Study.
1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Boston, Mass: Blackwell Science; 2003.
2. US FDA Center for Drug Evaluation and Research. Available at: http://www.fda.gov/cder/da/ddpab96.htm. Accessed March 18, 2003.
3. Lantus Consumer Information. Available at: http://www.fda.gov/cder/consumerinfo/druginfo/lantus.htm. Accessed March 18, 2003.
History of Sanofi in Diabetes:
1923 First Announcement of Insulin Hoechst....
History of Sanofi in Diabetes:
Insulin production 1939............ and Today
Sanofi today: developing agents to bring A1C
under control
Rapid-acting insulin analog
Once-daily basal insulin
Oral anti-diabetes agent
Early initiation of insulin is facilitated by simple dose titration
algorithms with insulin glargine
More patients achieved ≥2 consecutive HbA1c ≤6.5% and ≤7.0% with
insulin glargine + OHAs vs. an optimized OHA regimen
Glargine
OHA
p=0.0006
Patients (%)
p=0.032
24-week randomized study in 405 patients with T2DM to compare initiation + self-titrated (1 IU/day) evening
insulin glargine and physician-adjusted conventional OHA therapy – Target FPG>5.5 mmol/L [99 mg/dL]
1. Gerstein HC et al. Diabet Med 2006;23:736–742
Place of premixed insulins

Premixed insulins are not recommended
 For initiation or during adjustment of doses

If the proportion of rapid- and intermediate-acting insulin
is similar to the fixed proportions available
 Can be used before breakfast and/or dinner
Nathan DM, et al. Diabetes Care 2009;32 193-203.
Potential limitations of premixed insulin
analogues in clinical practice

Lack of flexibility: ratio of the 2 insulin components
cannot be adjusted separately
 Structured meal content and timing needed

No flexible regimen of self-titration

Regimens based on carbohydrate counting difficult to
devise

Insulin coverage may not address early-morning and/or
postlunch hyperglycemia

Not suitable when food intake is held (eg, in the inpatient
setting)
Rizvi AA, et al. Insulin 2007;2:68–79.
What are the SoloStar key features?

Disposable pen

Easy to give large doses, with 80 units maximum dose

Dose setting in 1 unit steps

Easy to set and adjust

Easy to read dose numbers

Easy to feel and hear clicks when dialing

Easy to push, soft and gentle injection

Easy to confirm dose delivery, dose window returns to ‘0’ confirming the dose is
delivered

Easy to differentiate Lantus and Apidra, for increased safety
So little can go wrong
with SoloStar that the
first check in most cases
of problems should be to
change the needle and
trying a safety test.
Since needle re-use is
common in many
markets, blocked
needles will very likely
be the biggest source of
user problems!
Safety test is also
known as ‘priming’, ‘air
shot’, etc. in various
markets.
However, these
alternate names miss
the point that a key
aim of the test is
making sure that the
needle is not blocked
and everything is
working properly, not
just removing air gaps.
Not understanding the
purpose of the test is
likely a key contributor
to how little it is done,
and therefore the large
number of calls we
receive that turn out to
be because of blocked
needles
Counting to 10
before withdrawing
the needle is
important. Small
amounts of insulin
continue to be
delivered during this
time as the bung
and any air bubbles
decompress. The
user will notice this
as insulin coming
out of the needle
after it is withdrawn
from the skin, and
this can result in
uncertainty about
the dose taken.
This is a step that is
commonly skipped
or reduced, so is
important to teach
well.
Patients prefer disposable Solostar® pen
“SoloStar® is an intuitive device – patients who have never seen
an insulin pen before can very easily and quickly learn how to use it1”
% of patients
Proportion of patients with an overall preference (first choice) for
Solostar, FlexPen or LillyPen2
SoloStar
FlexPen
Lilly
Disposable
Pen type
*p<0.05 vs. FlexPen: †p<0.05 vs. Lilly disposable pen
1. Clarke A et al. Exp Opin Drug Del 2007;4(2):165–174
2. Haak T et al. Clinical Therapeutics 2007;29:650–660
No
Preference
None
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