Endocrine

Advances in the treatment of Type 2 DiabetesThe 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 acid-sensitive 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.

UsageMixing with other insulin preparationsUnlike 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 HospitalOther informationDevelopmentThe development of Lantus was conducted at Sanofi-Aventis's biotechnology competence center in Frankfurt-Hцchst. 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-Hцchst 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-Hцchst.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 glargine-treated 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 linkOn 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 linkType 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

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
1
Gly
2
Ile
3
Val
4
Glu
5
Gln
6
Cys
7
Cys
8
Thr
9
Ser
10
Ile
11
Cys
12
Ser
13
Leu
14
Tyr
15
Gln
16
Leu
17
Glu
18
Asn
19
Tyr
20
Cys
21
Gly
1
Phe
2
Val
3
Asn
4
Gln
5
His
6
Leu
7
Cys
8
Gly
9
Ser
10
His
11
Leu
12
Val
13
Glu
14
Ala
15
Leu
16
Tyr
17
Leu
18
Val
19
Cys
20
Gly
21
Glu
22
Arg
23
Gly
24
Phe
25
Phe
26
Tyr
27
Thr
28
Pro
29
Lys
30
Thr
A chain
B chain
S
S
S
S
S
S
Asn
31
Arg
32
Arg
Addition
Addition
Deletion
Gly
Ile
3
Val
4
Glu
5
Gln
6
Cys
7
Cys
8
Thr
9
Ser
10
Ile
11
Cys
12
Ser
13
Leu
14
Tyr
15
Gln
16
Leu
17
Glu
18
Asn
19
Tyr
20
Cys
21
Gly
1
Phe
2
Val
3
Asn
4
Gln
5
His
6
Leu
7
Cys
8
Gly
9
Ser
10
His
11
Leu
12
Val
13
Glu
14
Ala
15
Leu
16
Tyr
17
Leu
18
Val
19
Cys
20
Gly
21
Glu
22
Arg
23
Gly
24
Phe
25
Phe
26
Tyr
27
Thr
28
Pro
29
Lys
30
Thr
S
S
S
S
Asn
31
Arg
32
Arg
Addition


Insulin glargine is the first basal insulin analogueIts extensive clinical development program shows that once-daily insulin glargine consistently allows HbA1c levels to be reduced to <7% in patients with T1DM or T2DM1–6Evidence 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 insulinsSmaller insulin dose (-77%) than detemir16A minimal impact on weight10–14The 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;21:1213–12202. Gerstein H et al. Diabet Med 2006;23:736–7423. Riddle M et al. Diabetes Care 2003;26:3080–30864. Bretzel RG et al. Diabetes 2006;55(suppl). Abstract 326–OR5. Yki-Jarvinen H et al. Diabetes Care 2007;30:1364–13696. Bergenstal R et al. Diabetes 2006;55(suppl). Abstract 441–P7. Rosenstock J et al. Diabetes Care 2005;28:950–9558. Mullins P et al. Clin Ther 2007;29:1607–1619 9. Janka H et al. Diabetes Care 2005;28:254–25910. Schreiber S et al. Diabetes Obesity Metab 2007;9:31–3811. Yki-Jarvinen H et al. Diabetes Care 2000;23:1130–113612. Fritsche A et al. Ann Int Med 2003;138:952–95913. Yki-Jarvinen H et al. Diabetologia 2006;49:442–45114. Rosenstock J et al. Diabetes Care 2006;29:554–55915. Lepore M et al. Diabetes 2000;49:2142–214816. Rosenstock J et al. Diabetologia 2008;51:408–416

These pharmacodynamic properties are clinically translated into:Once-daily administration1Effective lowering of FBG and PPBG over 24 hours when compared with NPH2 and premix 70/303 insulinsInsulin 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 diabetes6These features allow efficient and safe initiation of insulin therapy in patients with T2DM uncontrolled on OHAs5, 7, 3 1. Lantus Prescribing Information2. Yki-Jarvinen H et al. Diabetes Care 2000;23:1130–11363. Janka H et al. Diabetes Care 2005;28:254–2594. Standl E et al. Hormone Metab Res 2006;38:172–1775. Gerstein HC et al. Diabet Med 2006;23:736–7426. Davies M et al. Diabetes Care 2005; 28:1282–12887. Riddle M et al. Diabetes Care 2003;26:3080–3086

Properties of the ideal basal insulin

Peakless profile1 Long duration of action1 Flexible dosing Simple titration Suitable for treat-to-target schedules
1. Rosenstock J. Clin Cornerstone 2001;4:50–64. 0 4 8 12 16 20 24
Hours post dose
Insulin level

Hours post dose

Insulin level
0
4
8
12
16
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
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. Hours post dose
Insulin level
0
4
8
12
16
20
24
Insulin analogue (long acting)
Human insulin (intermediate acting)



Don’t ForgetInsulin 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
Duration
Up to 18 hrs
22-26 hrs
9-24 hrs (detemir); 20-24 hrs (glargine)
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  glycosuriaHypoglycemiaRates 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-yearsType 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

FPG, fasting plasma glucose Nathan DM, et al. Diabetes Care 2009;32:193-203.
CheckFPGdaily
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 Bedtime or morning long-acting insulin OR Bedtime intermediate-acting insulin Daily dose: 10 units or 0.2 units/kg
INITIATE
Increase dose by 2 units every 3 days 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 TITRATE
Continue regimen and check HbA1c every 3 months
MONITOR


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 The mechanics of sustained release1,2
Insulin glargine: the first long-acting insulin analogue
1. Bell DSH. Drugs 2007;67:1813–18272. McKeage K et al. Drugs 2001;61:1599–1624 3. Kramer W. Exp Clin Endocrinol Diabetes 1999;107(suppl 2):S52–S61 The mechanics of sustained release1,2

The 24-hour peakless action profile of insulin glargine allows once-daily injection

1. Lepore M et al. Diabetes 2000;49:2142–2148 Glucose infusion rate (mg/kg/min)
Time (hours)
0
4
8
20
16
12
24
Ultralente
CSII Lispro
NPH
Glargine
Flat action profile lasting for 24 hours
sc injection0.3 IU/kg or CSII 0.3 IU/kg/24/h
Rates of glucose infusion needed to maintain plasma glucoseat 130 mg/dL [7.2 mmol/L] after sc injection in patients with T1DM (n=20)

Basal insulin analogues

2. Porcellati F, et al. Diabetes Care 2007;30:2447–52.
Glucose infusion rate (mmol/kg/min)


Time (hours)
0
8
16
4
12
20
24
0
2
4
1
3
0
4
8
12
16
20
24
SC injection0.35 IU/kg
T1DM patients (n=24)2
Insulin detemir
Insulin glargine



1. Porcellati F et al. Diabet Med 2004;21:1213–12202. Gerstein H et al. Diabet Med 2006;23:736–742 3. Riddle M et al. Diabetes Care 2003;26:3080–3086 HbA1c is reduced ≤7% with once-daily insulin glargine T1DM
T2DM
Insulin glargine + OHAs
Basal-Bolus
Basal-Bolus
HbA1c (%)
12 months (n=61) p<0.05 vs. NPH
24 weeks (n=206)p=0.0007 vs. conventional therapy
24 weeks (n=367) p=ns vs. NPH
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–OR5. Yki-Jarvinen H et al. Diabetes Care 2007;30:1364–13696. Bergenstal R et al. Diabetes 2006;55(suppl). Abstract 441–P 2
1
4
3
6
5



Significantly more patients reach HbA1c target without nocturnal hypoglycemia with insulin glargine
1. Riddle M et al. Diabetes Care 2003;26:3080–3086 Patients (%)
p<0.05
NPH
Glargine
Mean HbA1c (%)
0
4
8
20
16
12
24
Final dose: Glargine 47 IU NPH 42 IU
Weeks
Target HbA1c %
24-week study comparing bedtime once-daily glargine or NPH in addition to OHAs in 756 insulin-naϊve patients with T2DM HbA1c ≤7% without documented nocturnal hypoglycemia

Insulin glargine consistently reduces hypoglycemia in T2DM vs. NPH

1. Rosenstock J et al. Diabetes Care 2005;28:950−955 Patients with hypoglycemia (%)
Overallhypoglycemia
Severehypoglycemia
Severe nocturnalhypoglycemia
RR=11%, p=0.0006
RR=46%, p=0.0442
RR=59%, p=0.0231
Meta-analysis of four randomized studies comparing insulin glargine to once-or twice-daily NPH in 2,304 patients with T2DM
NPH
Glargine



For any level of HbA1c, hypoglycemic event rates are lower with insulin glargine than NPH in T1DM
1. Mullins P et al. Clin Ther 2007;29:1607–1619 p-value (between Treatments): 0.004
6
7
8
10
9
LOCF HbA1c %
Hypoglycemic events per 100 patient-years
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
NPH
Glargine

1. Mullins P et al. Clin Ther 2007;29:1607–1619 p-value (between Treatments): 0.021

6
7
8
10
9
LOCF HbA1c %
Hypoglycemic events per 100 patient-years
For any HbA1c level, hypoglycemic event rates are lower with insulin glargine than NPH in T2DM
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
NPH
Glargine

Similar effect on weight as comparators in clinical studies

Yki-Jarvinen1
Treat-to-Target2
Fritsche3
LANMET4
LAPTOP5
Triple Therapy6
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 Mean weight gain (kg)
ns
p=0.02
Glargine bedtime
Glargine morning
Premix
Rosiglitazone
NPH

Premixed human insulin 30/70 BID

Insulin glargine provided better glycaemic control with fewer hypoglycemia than premix in elderly patients
p=0.003
Janka H, et al. J Am Geriatr Soc 2007;55:182−8. –1.4 –1.9 Change from baseline (%)
HbA1c
Incidence (episodes/patient-year)
10 8 6 4 2 0
Hypoglycaemia
p<0.008
3.7
9.1
Sub-population of patients aged ≥65 years (n=130) 0–0.5–1.0–1.5–2.0 Insulin glargine was well titratedand more effective
Insulin glargine was associatedwith fewer hypos
Insulin glargine

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” 1. Standl E et al. Hormone Metab Res 2006;38:172–177 Proportion of patients (%)
Proportion of patients (%)
Morning
Bedtime
Frequency of nocturnal hypoglycemia
Patients achieving HbA1c ≤7% No difference between morning and bedtime treatment arms
24-week, randomized study comparing evening to morning insulin glargineinjection in 624 patients with T2DM poorly controlled on OHAs

Basal, prandial and premixed insulin have different action profiles

Basal insulin Reduces fasting hyperglycaemia Long durationof action Inject morning and/or evening
Prandial insulin Reduces postprandial hyperglycaemia Short durationof action Inject at mealtimes
Premixed insulin Reduces fasting and postprandial hyperglycaemia Long biphasicduration of action Inject at mealtimes
0 4 8 12 16 20 24
Hours post dose
Insulin level
0 4 8 12 16 20 24
Hours post dose
Insulin level
0 4 8 12 16 20 24
Hours post dose
Insulin level
1. Rave K, et al. Diabetes Care 2006;29:1812–7.2. Becker RHA, et al. Exp Clin Endocrinol Diabetes 2005;113:435–43.


RANDOMISATION
Patients with T2DM HbA1c: 7.5% to 10.5%and FBG: ≥6.7 mmol/L (≥120 mg/dL) and treated with OHAs(n = 364) 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
Screening
24 weeks
Run-in phase
3–14 weeks LAPTOP study: Comparison of insulin glargine added to an OHA regimen versus switching to premixed insulin
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.

4
6
8
10
12
14
16
Endpoint
Fasting
Afterbreakfast
Lunch
After lunch
Dinner
After dinner
Bedtime
03.00
Significantly greater reduction in FBG and PPBG with insulin glargine vs premix
*
*
*
*
*
Blood glucose (mmol/L)
Baseline
Insulin glargine + OHAs
Premixed insulin twice daily
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.


Premixed insulin† Insulin glargine‡ 0 -0.5 -1.0 -1.5 -2.0
-1.31
Insulin glargine provided better glycaemic control and less weight gain than premix
Premixed insulin† Insulin glargine‡ Weight gain (kg)
1.4
2.1
2.5 2.0 1.5 1.0 0.5 0
-1.64
HbA1c change from baseline (%)
Final daily dose: Premixed insulin 64.5 IU Insulin glargine 28.2 IU
p = 0.0003
p = NS
†Twice daily; ‡plus OHAs Janka H, et al. Diabetes Care 2005;28:254–9.

0.51

0
2
4
6
8
10
12
Lower incidence of hypoglycaemia with insulin glargine versus premix
Events per patient per year
Premixed insulin Insulin glargine*
All confirmed hypoglycaemia
Confirmedsymptomatic
Confirmednocturnal
p < 0.0001
p = 0.0009
p = 0.0449
Hypoglycaemia confirmed by blood glucose <60 mg/dL (3.3 mmol/L)
Janka H, et al. Diabetes Care 2005;28:254–9. *Plus OHAs
1,04
2,62
9.87
5.73
4.07

Final dose (U/kg):

Glargine od
0.44
Detemir od or bid
0.78
Detemir vs. glargine in T2DM: same clinical outcomes but detemir at a higher daily dose and bid in most patients
1. Rosenstock J et al. Diabetologia 2008;51:408–416
+77%
HbA1c (%)
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%)
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Treatment time (weeks)
Glargine
Detemir

Rate of hypoglycemia was similar between the two treatment arms

55
Glargine
Detemir
0
25
50
75
100
Patients receiving 2 injections (%)
0
Glargine and detemir are equally effective but detemir requires higher doses and often two injections
Detemir
0.25
0.50
0.75
1.00
0.00
0.44
0.78
Glargine
Mean dose (U/kg)
Rosenstock J, et al. Diabetologia. 2008;51(3):408-416.



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.
Relative Risk
A1C (%)
15
13
11
9
7
5
3
1
6
7
8
9
10
11
12
A1C Complications
Retinopathy
Nephropathy
Neuropathy
Microalbuminuria
20

Initial Insulin Delivery Device

Lantus SoloStar

What are the SoloStar components?

1%
Lessons from UKPDS:Better control in T2DM means fewer complications
*p<0.0001 n=3,642 type 2 diabetes patients1. Stratton IM et al. BMJ 2000;321:405–412 Deaths from diabetes
Myocardial Infarction
Microvascular complications
Peripheral vascular disorders
-21%
-14%
-37%
-43%
Risk reduction*
1% reduction in HbA1c

Change over time in guidelinesfor evaluating hyperglycemia

Time period
Type of guideline
FBG (mg/dL)
FPG (mg/dL)
HbA1c (%)
<1993 (pre-DCCT)
Threshold for initiating or changing treatment
200
-
9-10
>1993 (post-DCCT)
Threshold for initiating or changing treatment
140
150
8
1997 to present
Recommended treatment goals (UKPDS)
80-120
90-130
<7
New diagnostic criteria for diabetes
-
126 -
2000
Definition of normoglycemia
99 109 <6
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
<7.0
IDF
≤6.5 NICE
<6.5
AACE
≤6.5 France
<6.5*
Canada
≤7.0 Australia
≤7.0 Latin America
<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 levelin 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
Turner R, et al. Ann Intern Med. 1996;124:136-145.
DCCT conventional
UKPDS conventional
UKPDS intensive
DCCT intensive
Time (y)
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
HbA1c (%)

Risk of complicationsBenefits of lowering hemoglobin HbA1c

0
4
8
12
16
6
7
8
9
10
11
12
Hemoglobin HbA1c (%)
Relative Risk of complications
Adapted from UKPDS 33: Lancet 1998;352:837-853. Adapted from DCCT Study Group. N Engl J Med 1993;329:977.
Average Glucose mg/dl
120
150
180
210
240
270
300

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 helpall 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 inthe 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 therapyIn general: HbA1c <7%In the individual patient: HbA1c as close to 6% as possible without significant hypoglycemiaCall to action: HbA1c 7%Less stringent goals may be appropriate for: Patients with a history of severe hypoglycemiaPatients with limited life expectanciesVery young children or older adultsIndividuals with co-morbid conditions Nathan DM, et al. Diabetes Care 2009;32 193-203.

Principles in selecting antihyperglycemic interventions

Effectiveness in lowering blood glucoseWhen high HbA1c (≥8.5%)Classes with greater and more rapid glucose-lowering effectiveness are recommendedPotentially earlier initiation of combination therapyExtraglycemic effects that may reduce long-term complicationsHypertension, dyslipidemia, BMI, insulin resistance, insulin secretory capacitySafety profilesTolerabilityEase of use Nathan DM, et al. Diabetes Care 2009;32 193-203.

ADA/EASD consensus algorithmOverarching principles

Early interventionPatient’s empowermentEducation, SMBG, treatment adjustmentShorten delays in treatment changesAchieve and maintain normal glycemic goalsAdd medications, transition to new regimens quicklyWhenever HbA1c levels are ≥7%STEP 1: Lifestyle intervention + metforminSTEP 2: Add another agent – basal insulin or SUSTEP 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 accordingto intervention

Intervention
Expected ↓ in HbA1c (%) Lifestyle interventions
1
to
2%
Metformin
1
to
2%
Sulfonylureas
1
to
2%
Insulin
1.5
to
3.5%
Glinides
1
to
1.5%1
Thiazolidinediones
0.5
to
1.4%
-Glucosidase inhibitors 0.5
to
0.8%
GLP-1 agonist
0.5
to
1.0%
Pramlintide
0.5
to
1.0%
DPP-IV inhibitors
0.5
to
0.8%
1. Repaglinide is more effective than nateglinide Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.


ADA/EASD consensus algorithm
At diagnosis: Lifestyle + Metformin
Lifestyle + Metformin + Basal insulin
Lifestyle + Metformin + Sulfonylurea
Lifestyle + Metformin + Intensive insulin
Tier 1:well-validated therapies
STEP 1
STEP 2
STEP 3
Call to action if HbA1c is 7% Tier 2:Less well validated therapies
Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss
Lifestyle + Metformin + Pioglitazone + Sulfonylurea
Lifestyle + metformin + Basal insulin
Lifestyle + metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.

Traditional approaches for intensifying insulin therapy: basal-bolus and premixed insulin

Hirsch I, et al. Clin Diabetes 2005;23:78−86. Lifestyle modification and OHAs
Basale.g. insulin glargine
Premixed insulin x1
Basal–boluse.g. insulin glargine + insulin glulisine x3 Premixed insulin x2
Premixed insulin x3

New approaches for intensifying insulintherapy: basal-plus

Basale.g. insulin glargine
Premixed insulin x1
Premixed insulin x3
Basal–boluse.g. insulin glargine + insulin glulisine x3 Premixed insulin x2
Basal-pluse.g. insulin glargine + insulin glulisine x1
Basal-pluse.g. insulin glargine + insulin glulisine x2
Lifestyle modification and OHAs
As per ADA/EASD guidelines

Basal plus Basal + 1 prandial

A logical stepwise approach
Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257.
Basal insulin once daily (treat-to-target)
Basal plus Basal + 2 prandial
Basal bolus Basal +3 prandial
Lifestyle+Metformin

HbA1c ≥7.0%, FBG on targetPPG ≥160 mg/dL HbA1c ≥7.0% Time

ADA/EASD consensus algorithm

At diagnosis: Lifestyle + Metformin
Lifestyle + Metformin + Basal insulin
Lifestyle + Metformin + Sulfonylurea
Lifestyle + Metformin + Intensive insulin
STEP 1
STEP 2
STEP 3
Tier 1: Well-validated therapies
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.
These interventions represent the best established and most effective and cost-effective therapeutic strategy for achieving the target glycemic goals

Attributes of metformin

How it works
Decreases hepatic glucose output
Lowers fasting glycemia
Expected HbA1c reduction
1 to 2% (monotherapy)
Adverse events
GI side effects
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
* p<0.05** p<0.01†p<0.001 vs placebo Garber AJ, Am J Med 1997;102:491-7.
*
**
† † (mg/dL)
Metformin Dose
- 20
- 40
- 60
- 80
Change vs. placebo (mmol/L)
mg
HbA1c
† † Metformin Dose
Change vs. placebo (%)
mg
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
† † † †


ADA/EASD consensus algorithm: step 2
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
At diagnosis: Lifestyle+Metformin
Lifestyle + Metformin + Basal insulin
Lifestyle+ Metformin + Sulfonylurea
STEP 1
STEP 2
HbA1c 7% When HbA1c is high (>8.5%), classes with greater and more rapid glucose-lowering effectiveness, or potentially earlier initiation of combination therapy, are recommended

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

* 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.
How they work
Enhance insulin secretion
Expected HbA1c reduction
1 to 2%
Adverse events
Hypoglycemia* (but severe episodes are infrequent)
Weight effects
~ 2 kg weight gain common when therapy initiated
CV effects
None substantiated by UKPDS or ADVANCE study

Adding sulfonylurea to metformin is particularly effective in lowering HbA1c

Glyb: glyburide TZD: thiazolidinedione Repag: repaglinide SU: sulfonylurea Met: metformin Bolen S, et al. Ann Intern Med 2007;147:386-399.
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
-1.5
-1.0
-0.5
0
0.5
Drug 1 more beneficial
Drug 1 less beneficial
Weighted mean difference in HbA1c Value, %
Drug 1

ADA/EASD consensus algorithm: step 2Insulin initiation

At diagnosis: Lifestyle+Metformin
Lifestyle + Metformin + Basal insulin
Lifestyle+ Metformin + Sulfonylurea
STEP 1
STEP 2
HbA1c 7% HbA1c 7% Nathan DM, et al. Diabetes Care 2009;32 193-203.

How it works

Direct compensation for lack of insulin sensitivity
Expected HbA1c reduction
1.5 to 3.5%
No maximum dose +++
Adverse events
Hypoglycemia
Weight effects
Weight gain of ~ 2–4 kg CV effects
Beneficial effect on TG and HDL
Weight gain may have an adverse effect on CV risks
Attributes of insulin
HDL: TG: triglycerides CV: cardiovascular Nathan DM, et al. Diabetes Care 2009;32:193-203.


History of Diabetes: milestones in diabetes treatment
Insulin glargine
Insulin discovered
First sulphonylureas
NPH insulin
Lente insulins
Metformin
Insulin pump
Rapid-acting insulin
UKPDS
1920
1940
1960
1980
2000
A1C
DCCT
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

Once-daily basal insulin

Oral anti-diabetes agent
Rapid-acting insulin analog


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 1. Gerstein HC et al. Diabet Med 2006;23:736–742 Patients (%)
Glargine
OHA
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] p=0.032
p=0.0006

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 penEasy to give large doses, with 80 units maximum doseDose setting in 1 unit stepsEasy to set and adjustEasy to read dose numbersEasy to feel and hear clicks when dialingEasy to push, soft and gentle injectionEasy to confirm dose delivery, dose window returns to ‘0’ confirming the dose is deliveredEasy 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.

“SoloStar® is an intuitive device – patients who have never seen an insulin pen before can very easily and quickly learn how to use it1”
*p<0.05 vs. FlexPen: †p<0.05 vs. Lilly disposable pen1. Clarke A et al. Exp Opin Drug Del 2007;4(2):165–1742. Haak T et al. Clinical Therapeutics 2007;29:650–660 Proportion of patients with an overall preference (first choice) for Solostar, FlexPen or LillyPen2
SoloStar
FlexPen
Lilly Disposable
NoPreference
None
Pen type
% of patients

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