1. The reality of basal insulin therapy and clinical inertia
Speaker name and affiliation
Prescribing information is available on the last slides
UK/GLA/00142a April 2016

2. Agenda and learning points
Understand the requirement for insulin-replacement therapy in type 2 diabetes.
Know what insulin your patients may already be on, and why.
Review the available basal insulins.
Look at the degree of clinical inertia associated with basal-insulin initiation and optimisation.
Understand what optimisation and intensification means in practice.
Recognise the right time for optimisation and intensification for each patient.

3. The reality of basal-insulin therapy
When a basal regimen is not achieving the goals of therapy

4. The impact of diabetes

5. Cost to the NHS of diabetes*
£2.1bn
£7.7bn
Cost of diabetes treatment
Cost of treating complications
Key Points
The raw cost of diabetes is £9.8bn, 80% of which is spent on complications that can be avoided! This slide has one simple animation.
≈ 80% of NHS spending on diabetes goes on AVOIDABLE complications!
* Estimated costs for 2010 ⁄ 2011 from aggregated data sets and literature
Hex N et al. Diabet Med. 2012; 29:

6. Direct cost to NHS of diabetes
Key point
The substantial part of direct costs for diabetes treatment is the cost of primary care time and effort.
This time must be better used if the increasing burden of type 2 diabetes is to be managed effectively
The amount spent on education is also worryingly small!
What can be done to optimise the impact of this valuable healthcare resource?
Additional narrative
The NHS funding gap between expected costs and expected resources is huge up to 20/21at least £5 bn anuually up to 2021.
Proposals to fill this gap target changes centred on:
Improving productivity within existing services
Delivering the right care in the right setting
Developing new ways of delivering care
Allocating spending more rationally
However, filling this gap isn’t just about upskilling HCPs around therapies to provide more effective care, but is also about empowering the patient to take responsibility for their condition by approaching the interaction differently. So this workshop is intended to look at both aspects of management.
* Estimated costs for type 1 & type 2 diabetes 2010 ⁄ 2011 from aggregated data sets and literature
Hex N et al. Diabet Med. 2012; 29:

7. Between 2007 – 2012, avoidable complications increased significantly
67%
130%
106%
Cardiac failure
Angina
Stroke
Diabetes UK, STATE OF THE NATION Challenges for 2015 and beyond – England
Key Points
The prevalence of avoidable complications of diabetes is increasing
Each year, around 20,000 people with diabetes die early
People with diabetes are also at a greater risk of developing one or more severe health complications
Diabetes is:
responsible for more than 100 amputations a week
the leading cause of preventable sight loss in people of working age
a major contributor to kidney failure, heart attack, and stroke
Copyright permission requested.
33%
95%
60%
Retinopathy
Renal replacement therapy
Amputations
Diabetes UK, STATE OF THE NATION Challenges for 2015 and beyond. Found at: [Accessed June 2015]

8. The reward for improved control
Every 1% reduction in HbA1c
14%
Fatal or non-fatal MI
REDUCED RISK 1%
21%
Deaths from diabetes
37%
UKPDS
In type 2 diabetes, the UKPDS investigated 5,102 patients with newly diagnosed type 2 diabetes and proven beyond doubt that intensive glycaemic control is strongly associated with significant clinical benefits for patients with type 2 diabetes.
UKPDS allows us to conclude that every 1% decrease in HbA1c can be associated with clinically significant reductions in the incidence of:
Fatal or non fatal myocardial infarction by 14%
diabetes-related death, by 21%
of microvascular complications, 37%
and of peripheral vascular disease, by 43%
Reference
UKPDS 35: BMJ 2000, 321:
Microvascular complications
43%
Amputation or death from peripheral vascular disorders
Adapted from: Stratton IM et al. BMJ 2000; 321:
Adapted from: UKPDS 35: BMJ 2000, 321:

9. The reality of diabetes and insulin therapy

10. The inevitable progression to insulin therapy
Years
Glucose (mmol/L)
Relative Function
(% of Normal)
-15
-10 5 10 15 20 25 30
2.8
5.6
8.3
11.1
13.9
16.7
19.4
Clinical Diagnosis
Insulin resistance
Insulin Response
Postprandial glucose
FPG
Prediabetes (IFG, IGT) 50
100
150
200
250
Clinical diagnosis
Obesity, Inactivity,
Genetics
Onset of
diabetes -5
Data from Simonson et al
Key Points:
These are the typical patterns of progression for glucose levels, insulin resistance, and beta-cell function in patients with type 2 diabetes.1
A characteristic finding in type 2 diabetes is insulin resistance; insulin resistance is thought to be influenced by genetic and, perhaps, congenital factors and may be augmented by acquired or environmental factors, such as obesity, sedentary lifestyle, and ageing1,2
Background:
Although there is controversy over the primary defect, most studies support that insulin resistance and hyperinsulinaemia precedes type 2 diabetes.3
In the early stages of type 2 diabetes, glucose levels remain normal due to increased insulin secretion (hyperinsulinaemia) via compensating beta cells; however, over time, beta cells can no longer compensate to maintain a hyperinsulinaemic state, leading to increased levels of postprandial glucose (PPG) and increased hepatic glucose production, further decreases in insulin secretion due to beta-cell failure, and, ultimately, overt development of Type 2 diabetes.1,3
Stages of progression (as shown on slide)1
Prediabetes: Most studies support that insulin resistance precedes hyperglycaemia; in the early stages of Type 2 diabetes, glucose levels remain normal due to increased insulin secretion (hyperinsulinaemia) via compensatory beta cells1,3
Clinical diagnosis: Over time, beta cells can no longer compensate by maintaining a hyperinsulinaemic state, leading to increased levels of PPG and increased hepatic glucose production1,3
Overt Type 2 diabetes: Continued decline in beta-cell function and insulin resistance result in overt diabetes, with elevated fasting plasma glucose (FPG) levels above 6.9 mmol/l.1,3
References:
1. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005;16(8):
2. Zimmet P, Alberti KGMM, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414(6865):782-7.
3. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;88(4):
FPG=Fasting Plasma Glucose; IFG=Impaired Fasting Glucose; IGT=Impaired Glucose Tolerance
Reviewed in: Simonson GD and Kendall DM. Coron Artery Dis 2005; 16:

11. The inevitable trajectory of type 2 diabetes
Eventually all patients will require insulin to be initiated and increased incrementally with progression of disease.
250
Insulin resistance
200
Relative Function
(% of Normal)
150
100
Key Points:
These are the typical patterns of progression for glucose levels, insulin resistance, and beta-cell function in patients with type 2 diabetes.1
A characteristic finding in type 2 diabetes is insulin resistance; insulin resistance is thought to be influenced by genetic and, perhaps, congenital factors and may be augmented by acquired or environmental factors, such as obesity, sedentary lifestyle, and ageing1,2
Background:
Although there is controversy over the primary defect, most studies support that insulin resistance and hyperinsulinaemia precedes type 2 diabetes.3
In the early stages of type 2 diabetes, glucose levels remain normal due to increased insulin secretion (hyperinsulinaemia) via compensating beta cells; however, over time, beta cells can no longer compensate to maintain a hyperinsulinaemic state, leading to increased levels of postprandial glucose (PPG) and increased hepatic glucose production, further decreases in insulin secretion due to beta-cell failure, and, ultimately, overt development of Type 2 diabetes.1,3
Stages of progression (as shown on slide)1
Prediabetes: Most studies support that insulin resistance precedes hyperglycaemia; in the early stages of Type 2 diabetes, glucose levels remain normal due to increased insulin secretion (hyperinsulinaemia) via compensatory beta cells1,3
Clinical diagnosis: Over time, beta cells can no longer compensate by maintaining a hyperinsulinaemic state, leading to increased levels of PPG and increased hepatic glucose production1,3
Overt Type 2 diabetes: Continued decline in beta-cell function and insulin resistance result in overt diabetes, with elevated fasting plasma glucose (FPG) levels above 6.9 mmol/l.1,3
References:
8. Simonson GD, Kendall DM. Diagnosis of insulin resistance and associated syndromes: the spectrum from the metabolic syndrome to type 2 diabetes mellitus. Coron Artery Dis 2005;16(8):
9. Zimmet P, Alberti KGMM, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414(6865):782-7.
10. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 2004;88(4):
Prediabetes (IFG, IGT)
Clinical diagnosis
Clinical Diagnosis 50
Insulin Response
Onset of
diabetes
-15
-10 -5 5 10 15 20 25 30
Data from Simonson et al
Years
FPG=Fasting Plasma Glucose; IFG=Impaired Fasting Glucose; IGT=Impaired Glucose Tolerance
Reviewed in: Simonson GD and Kendall DM. Coron Artery Dis 2005; 16:

12. What are we trying to mimic with insulin therapy?
Breakfast
Lunch
Dinner
Normal insulin response to meals
Normal glucose response to meals
Glucose level (mg/dL)
Insulin level (μU/mL)
100 75 50 25
200
150
7 am
9 am
11 am
1 pm
3 pm
5 pm
7 pm
9 pm
Time
Prandial insulin
Basal insulin
Prandial glucose
Normal Physiology of Insulin and Glucose Response to Meals. In a nondiabetic individual, basal glucose levels range between 70 and 100 mg per dL while fasting. Basal glucose supplies the heart and central nervous system with an immediate and constant source of energy. Basal insulin levels prevent the liver from accelerating its release of glucose into the plasma via glycogenolysis and gluconeogenesis. If the patient is in the fed state, glucose levels will increase, triggering the pancreatic beta cells to release enough insulin to maintain postprandial glucose levels less than 140 mg per dL. Note that the basal and prandial glucose levels vary according to the time of day as well as the quantity and quality of consumed nutrients at any given meal. In the early morning hours, levels of circulating counterregulatory hormones (growth hormone and cortisol) are increased, resulting in a state of insulin resistance. A normally functioning pancreas overcomes this state of insulin resistance by secreting more insulin in response to these counterregulatory hormones. Therefore, insulin requirements are normally elevated in the morning. In the afternoon hours, insulin resistance is minimized, and insulin requirements decrease. Suppers tend to be the largest meal of the day, during which time one consumes the most calories, carbohydrates, and fats. The higher fat content in food will delay gastric emptying as well as the absorption of carbohydrates from the gut. Patients who must use exogenous insulin should attempt to replicate this complex interactive scheme to maintain blood glucose levels as near to normal as possible. Different basal and bolus-delivery patterns must be used to match this physiologic endogenous insulin milieu.
Basal glucose
Data from: 1. Krentz AJ and Bailey CJ. Type 2 Diabetes in Practice. The Royal Society of Medicine Press. London p12-25
2. Polonsky KS et al. N Engl J Med 1988; 318: 12 9

13. What does a normal postprandial glucose response look like?
Incremental blood glucose profiles for 6 food categories compared to glucose
Change in plasma glucose (mmol/L)
0.0
- 0.5
1.0
1.5
2.0
3.0
2.5
4.0
0.5
3.5
Time after ingestion (mins) 15 60 30 45 75 90
105
120
Glucose
Potatoes
White bread
Vegetables
Pasta/noodles
Legumes
Data from: Brand-Miller JC et al Am J Clin Nutr 2009; 89: 97–105

14. NG28 and basal-insulin treatment
National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 ( [Last Accessed: January 2016]. Reproduced with permission.

15. NG28 and basal-insulin treatment
National Institute for Health and Care Excellence. Type 2 diabetes in adults: management. NICE guideline 28. London: NICE; December 2015 ( [Last Accessed: January 2016]. Reproduced with permission.

16. Starting insulin: the 4-T Study
The Treating To Target in Type 2 diabetes (4-T) study was a three- year, multi-centre, open-label, randomised, parallel-group trial comparing the safety and efficacy of:
Analogue prandial insulin
Analogue basal insulin
Analogue biphasic insulin
In 700 participants with Type 2 diabetes inadequately controlled by oral therapy and starting insulin treatment.
Summary of 4-T study on insulin regimes
Patients who added a basal or prandial insulin-based regimen to oral therapy had better HbA1c control than patients who added a biphasic insulin-based regimen. Fewer hypoglycaemic episodes and less weight gain occurred in patients adding basal insulin.
Holman RR et al. N Engl J Med 2009; 361:

17. 4-T Study: Key Learning Points
Those commencing therapy with a basal or prandial insulin more often achieved glycaemic targets than patients commencing with a biphasic insulin
Approximately three quarters of patients added a second insulin
Patients commencing therapy with basal insulin had fewer hypoglycaemic episodes and less weight gain
These findings provide clear evidence in people with type 2 diabetes to support starting insulin therapy with a once a day basal insulin, and then adding a mealtime insulin if glycaemic targets are not met
Summary of 4-T study on insulin regimes
Patients who added a basal or prandial insulin-based regimen to oral therapy had better HbA1c control than patients who added a biphasic insulin-based regimen. Fewer hypoglycaemic episodes and less weight gain occurred in patients adding basal insulin.
Holman RR et al. N Engl J Med 2009; 361:

18. Potential basal insulin regimes

19. What basal-insulin might your patients with type 2 diabetes be on?7 6 5
Humulin I® (NPH insulin) 4
Levemir® (Insulin detemir)
Relative insulin effect 3
Lantus® & Abasaglar®* (Insulin glargine U100) 2 1
Speaker notes
The primary care delegates should know these basal-insulin brands and their time-action profiles, and what that means in clinical practice – i.e. risk of hypoglycaemia, or need for 2x injections with NPH in some people with T2D
This slide prompts a discussion about the time-action profiles of the established brands of basal insulin, again reiterating the biosimilarity between Lantus and Abasaglar. Refer back to slide 16 highlighting the basal insulin time-action profile in normal subjects. 3 6 9 12 15 18 21 24
Time (hours)
* Abasaglar, biosimilar insulin glargine U100
Levemir is a trademark of Novo Nordisk
Lantus is a trademark of Sanofi
Humulin I & Abasaglar are trademarks of Eli Lilly
Reviewed in: Bergenstal RM ‘Effective insulin therapy’ in International Textbook of Diabetes. 3rd Ed; 2004:

20. Abasaglar ®▼ (biosimilar insulin glargine)

21. What makes Abasaglar® a biosimilar?
A-chain
B-chain s
A-chain
B-chain
Same amino acid sequence
Sanofi Aventis
Differences in biotechnical manufacturing process
Lantus®
Similar medicine
Definitions of biosimilars:
The term “biosimilar” is largely a regulatory designation.
The amino acid sequence of a biosimilar therapeutic protein molecule should be confirmed and is expected to be identical to the previously marketed “reference” product (defined as a single authorised biological product against which a proposed biosimilar product is evaluated in its application for regulatory authorisation).1,2,3 The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) do not require the amino acid sequence to be exactly identical, but any minor differences should be shown to not affect safety or efficacy.2,3
A biological medicinal product derived from biotechnological manufacturing processes.1,3
A product showing no clinically meaningful differences in safety or efficacy from the reference product.2
References:
US Food and Drug Administration. Biosimilar biological products. Last accessed: April 2015.
US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Last accessed: April 2015.
European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). Last accessed: April 2015.
SPC2
Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.2
SPC1
Treatment of diabetes mellitus in adults, adolescents and children aged 2 years and above.1
Similar SPC
1. Abasaglar Summary of Product Characteristics. 2. Sanofi Aventis, Lantus Summary of Product Characteristics

22. Defining biosimilar medicines
A biosimilar is a medicine similar to an existing biological medicine
Biosimilars:
have an identical indication to the reference medicine
are produced in or derived from living systems (e.g. using recombinant DNA technology)
need to demonstrate that they are as safe and effective with the same quality as the original reference medicine
Due to their origin and process sensitivity, reference biological medicines and biosimilars have variations over time, which are monitored and reviewed by the EMA
Definitions of biosimilars:
The term “biosimilar” is largely a regulatory designation.
The amino acid sequence of a biosimilar therapeutic protein molecule should be confirmed and is expected to be identical to the previously marketed “reference” product (defined as a single authorised biological product against which a proposed biosimilar product is evaluated in its application for regulatory authorisation).1,2,3 The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) do not require the amino acid sequence to be exactly identical, but any minor differences should be shown to not affect safety or efficacy.2,3
A biological medicinal product derived from biotechnological manufacturing processes.1,3
A product showing no clinically meaningful differences in safety or efficacy from the reference product.2
References:
US Food and Drug Administration. Biosimilar biological products. Last accessed: April 2015.
US Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Last accessed: April 2015.
European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). Last accessed: April 2015.

23. Requirements to assure biosimilarity1
Similarity demonstrated in preclinical in vitro, in vivo, PD and toxicology studies  
Similarity demonstrated in clinical trials designed to assess PK and PD against standard acceptance limits 
No clinically meaningful differences in immunogenicity
Head-to-head clinical trial(s) to detect relevant differences in efficacy or drug-related safetya 
Abbreviations:
PD; pharmacodynamics
PK; pharmacokinetics
Notes
Immunogenicity describes the property enabling a substance to provoke an immune response. Immunogenicity may present potential issues with protein-based therapeutics, due to the development of an unwanted immune response, which could affect its efficacy and safety profile.1 This explains why the regulatory authorities have strict guidelines to assess the comparative immunogenicity between drugs.2
References:
eas/ucm htm Last accessed April 2015
/01/WC pdf Last accessed April 2015
a Efficacy/safety trial needed unless biosimilarity convincingly demonstrated by nonclinical, pharmacology, and immunogenicity studies
European Medicines Agency (EMA). Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues . Available at: (accessed April 2015).

24. Comparative Pharmacokinetics and Pharmacodynamics of 2 Insulin Glargine Products, Abasaglar and Lantus®, in Healthy Subjects at 2 Dose Levels
Zhang et al. ADA 2014: 890-P
BIV
Lantus is a registered trademark of Sanofi-Aventis

25. PD of Abasaglar® and Lantus® with 0.3 U/kg dosing*
Mean (± SD) Glucose Infusion Rate (Top) and Corresponding Glucose Levels (Bottom)
*Healthy subjects PD=pharmacodynamics; SD=standard deviation
Abasaglar 0.3 U/kg
Lantus 0.3 U/kg
BIV
There was no statistically significant difference in PD between LY IGlar and IGlar for the 0.3 U/kg dose (1.0 contained within 90% confidence interval), demonstrating that the PD of LY IGlar and IGlar are similar
Mean blood glucose levels were similar for LY IGlar and IGlar
The clamps were well conducted, as evidenced by the relatively flat mean blood glucose profiles at each dose level
Background
This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the pharmacokinetics and PD of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg)
The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level
Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each
A minimum 6-day washout separated doses
Zhang et al. ADA 2014: 890-P
Lantus is a registered trademark of Sanofi-Aventis 25

26. PK of Abasaglar® and Lantus® with different doses*
Mean (± SD) C-peptide-corrected Serum Insulin Concentration
Abasaglar (0.6 U/kg)
Abasaglar (0.3 U/kg)
Lantus 0.3 U/kg Lantus 0.6 U/kg
BIV
There was no statistically significant difference in PK between LY IGlar and IGlar for both doses (all the corresponding 90% confidence intervals of the ratios of geometric least squares means for the primary PK parameters of area under the concentration-time curve from time 0 to 24 hours and maximum observed drug concentration spanned 1)
Background
This Phase 1, single-site, randomized, subject- and investigator-blinded, 4-treatment, 4-period, crossover study evaluated the PK and pharmacodynamics of LY IGlar and IGlar at 2 different dose levels (0.3 and 0.6 U/kg)
The study was carried out to supplement the results of a larger, pivotal study at the 0.5 U/kg dose level
Fasted healthy subjects (N = 24; aged 23–52 years) were randomly assigned to 1 of 4 dosing sequences and received a total of 2 doses (0.3 and 0.6 U/kg) of LY IGlar and IGlar on 1 occasion each
A minimum 6-day washout separated doses
*Healthy subjects
PK=pharmacokinetics; SD=standard deviation
Linnebjerg et al. ADA 2014: 889-P
Lantus is a registered trademark of Sanofi-Aventis

27. The ELEMENT 2 Study: Similar Efficacy and Safety with Abasaglar Compared with Lantus® in Patients with T2DM
Rosenstock J et al. Diabetes Obes Metab  2015; 17:
BIV
Lantus is a registered trademark of Sanofi-Aventis

28. ELEMENT 2: Objectives Primary Key secondary
To demonstrate the non-inferiority of Abasaglar to Lantus® as measured by change in HbA1c from baseline to 24 weeks, when used in combination with OADs
Key secondary
Non-inferiority of Lantus to Abasaglar
Change in HbA1c over time
7-point SMBG
Fasting blood glucose changes over time (by SMBG)
Proportion of patients with HbA1c <7% or ≤6.5%
Change in body weight
Insulin dose
Hypoglycaemia
Adverse events
Incidence of anti-insulin antibodies
BIV
The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks, at the non-inferiority margin of +0.4%
If the 0.4% non-inferiority margin was met, then the upper limit of the 95% confidence interval was compared with the 0.3% non-inferiority margin to control for the family-wise type 1 error rate at a 1-sided level
Secondary objectives of ELEMENT 2 included the non-inferiority of IGlar to LY IGlar at the non-inferiority margin of −0.4%, safety, and additional measures of glycaemic control
If LY IGlar was declared non-inferior to IGlar in the primary treatment comparison, and IGlar was declared non-inferior to LY IGlar in the secondary treatment comparison, then LY IGlar was considered to have equivalent efficacy to IGlar
Background
ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus
The study included a 24-week treatment period and a 4-week post-treatment follow-up
The study population included both insulin-naïve patients uncontrolled on ≥2 OADs and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs
HbA1c=glycosylated haemoglobin; OAD=oral antidiabetic drug; SMBG=self-monitored blood glucose
Rosenstock J et al. Diabetes Obes Metab  2015; 17:
Lantus is a registered trademark of Sanofi-Aventis 28

29. ELEMENT 2: Change at Study End in HbA1c and % of Patients Reaching Target HbA1c
Lantus (n=268) Abasaglar (n=267)
Lantus
BIV
In the total population, the primary efficacy outcome was met, demonstrating non-inferiority of LY IGlar to IGlar for change in HbA1c at 24 weeks at 0.4% and 0.3% non-inferiority margins
Similar results were seen in the patient subpopulations who were either insulin-naïve or were on IGlar at study entry
In the total population, there were no statistically significant differences between treatment groups in the proportion of patients who achieved HbA1c target values of <7.0% and ≤6.5% at endpoint, supporting the primary endpoint analyses; similar results were seen in the patient subpopulations who were either insulin-naïve or were on IGlar at study entry
Background
ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus
The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks1
The study included a 24-week treatment period and a 4-week post-treatment follow-up
The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs
Abasaglar
(N = 379)
(N = 220)
(N = 155)
Lantus
(N = 375)
(N = 235)
(N = 144)
HbA1c=glycosylated haemoglobin; NS=not significant
Rosenstock J et al. Diabetes Obes Metab  2015; 17:
Lantus is a registered trademark of Sanofi-Aventis

30. ELEMENT 2: similar total, nocturnal and severe hypoglycaemia1
Abasaglar® (n=375)
Lantus® (n=379) 78 79
(72)
(72)
(75)
(75)
(67)
(67) 57 54 22 21 8 8
Data from Rosenstock J et al. Diabetes Obes Metab  2015; 17:

31. ELEMENT 2: similar incidence of Treatment-Emergent Antibody Response (TEAR)1
Abasaglar® (n=376)
Lantus® (n=380)
TEAR criteria
• If antibody was not detected at baseline
• If antibody was detected at baseline
% antibody binding ≥1.26%
absolute increase in % antibody binding of 1% and 30% relative increase from baseline
LOCF=last observation carried forward.
Data from Deeg MA et al. Diabetes Obes Metab  2016; 18(2):

32. ELEMENT 2: Summary
Abasaglar compared with Lantus demonstrated similar:
glucose-lowering effect (FBG, SMBG, HbA1c)
insulin doses
changes in body weight
hypoglycaemia incidence and rates
adverse-event profile
allergic and injection site reactions
incidence of treatment-emergent antibody response
BIV
LY IGlar was well tolerated, with similar safety profiles for LY IGlar and IGlar (hypoglycaemia, adverse-event profile, antibody responses)
There were no new safety findings in either treatment group
Background
ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus
The primary objective of ELEMENT 2 was to demonstrate the non-inferiority of LY IGlar to IGlar as measured by change in HbA1c from baseline at 24 weeks
The study included a 24-week treatment period and a 4-week post-treatment follow-up
The study population included both insulin-naïve patients uncontrolled on ≥2 oral antidiabetic drugs (OADs) and IGlar-treated patients either controlled or uncontrolled on ≥2 OADs
FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; SMBG=self-monitored blood glucose
Rosenstock J et al. Diabetes Obes Metab  2015; 17:

33. Clinical studies in T1D & T2D
Abasaglar compared with IGlar demonstrated similar:
ELEMENT 1
ELEMENT 2
Abasaglar
Lantus
Glucose-lowering effect: FBG, SMBG, HbA1c 1,2
Insulin doses1,2
Changes in body weight1,2
Hypoglycaemia incidence and rates1,2
Adverse-event profile1,2
Allergic and injection site reactions3
Incidence of treatment-emergent antibody response3    
Background
ELEMENT 1 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 1 diabetes mellitus
ELEMENT 2 was a global Phase 3 trial evaluating LY IGlar and IGlar in patients with type 2 diabetes mellitus
FBG=fasting blood glucose; HbA1c=glycosylated haemoglobin; SMBG=self-monitored blood glucose
Blevins T et al. Diabetes Obes Metab. 2015;17:
Rosenstock J et al. Diabetes Obes Metab  2015; 17:
Deeg M et al. ADA 2014: 70-OR

34. The imperative for basal-insulin optimisation

35. Clinical inertia in UK – HbA1c on OADs at the point of insulin initiation
81,573 patients from UK Clinical Practice Research Datalink database 6 7 8 9 10 11
Mean HbA1c at the point of insulin initiation (%) 5 4 3 2 1
Number of OADs prior to initiation
8.4%
8.8%
9.0%
Khunti K, et al. Diabetes Care 2013, 36:
This was a retrospective cohort study based on 81,573 people with type 2 diabetes in the U.K. Clinical Practice Research Datalink between January 2004 and December 2006, with follow-up until April 2011.
RESULTS:
In people with HbA1c ≥7.0, ≥7.5, or ≥8.0% (≥53, ≥58, or ≥64 mmol/mol), median time from above HbA1c cutoff to intensification with an additional OAD was 2.9, 1.9, or 1.6 years, respectively, for those taking one OAD and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6.0 years for those taking one, two, or three OADs. Mean HbA1c at intensification with an OAD or insulin for people taking one, two, or three OADs was 8.7, 9.1, and 9.7%. In patients taking one, two, or three OADs, median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was % and with insulin %.
OADs: oral antidiabetes drugs
Khunti K, et al. Diabetes Care 2013, 36:

36. Clinical inertia persists following initiation of basal insulin
UK Clinical Practice Research Datalink database
Aim: to estimate the likelihood of intensification, and time from starting basal insulin to intensification
Subcohort analysis
6072 patients ≥ 18 years old on basal-insulin only
HbA1c >58 mmol/mol ≥ 6 months following basal-insulin initiation
The median time to intensification = 3.7 years
Key points
Remember, as regards insulin initiation there is a culture of inertia such that:
The time between failure on OADs and the point of insulin initiation is 5 years for 50% of T2D patients1
The mean HbA1c at the point of initiation is % 2
Once initiated, optimisation and intensification also suffers from inertia3
There is also a culture of inertia in basal-insulin optimisation3
1. Rubino A et al. Diabetic Medicine 2007, 24:
2. Khunti K, et al. Diabetes Care 2013, 36:
3. Blak BT et al. Diabetic Medicine 2012, 29: e13-e20
Khunti K et al. Diabetes Obes Metab. 2016;  18:

37. Follow up of 6072 basal-only patients with T2D
Khunti K et al. Diabetes Obes Metab. 2016;  18:

38. 15% intensified to basal-bolus treatment
Khunti K et al. Diabetes Obes Metab. 2016;  18:

39. 13% intensified to twice-daily premix
Khunti K et al. Diabetes Obes Metab. 2016;  18:

40. 3% intensified with add-in GLP-1 RA
Khunti K et al. Diabetes Obes Metab. 2016;  18:

41. 21% achieved target HbA1c on basal only
Khunti K et al. Diabetes Obes Metab. 2016;  18:

42. 49% with HbA1c above 58 mmol/mol but not optimised or intensified
Khunti K et al. Diabetes Obes Metab. 2016;  18:

43. The unmet need for earlier optimisation and intensification of basal-insulin therapy
Patients with type 2 diabetes initiated on basal insulin are not optimised despite evidence of continued poor glycaemic control.
For patients who remain above HbA1c ≥ 7.5% (58 mmol/mol) on basal insulin the median time from initiation to intensification is 3.7 years.
This avoidable glycaemic exposure increases the risk of long-term microvascular and macrovascular complications and mortality.
Speaker notes
The summary slide provides further context in regards of the delays in intensification (3.7 years) and includes a ‘call-to-arms’ for improved strategies in this regard.
Strategies should be developed to increase the number of patients undergoing therapy intensification and to reduce the delay in intensifying therapy for suitable patients on basal insulin. Initiatives to support patients continuing on insulin are also required.
Khunti K et al. Diabetes Obes Metab. 2016;  18:

44. Why is basal-insulin control in type 2 diabetes not optimised?

45. Interactive exercise - small working groups
Discuss and quickly log on flip charts the possible reasons for poor basal-insulin control in type 2 diabetes . In doing so we would like you to separate these factors into 3 main areas.
Work quickly – you have 10 minutes for discussion and logging your thoughts.
Each group will have 2 minutes to briefly summarise the main
Environment (work/social)
HCP (clinical)
Workshop exercise & discussion
The slide describes the exercise and is designed to get delegates to start thinking about barriers that create inertia in treatment optimisation and also their own role as an HCP in this context – how much are they ‘part of the problem’? The whole exercise can be concluded in a period.
Patient (behaviour)

46. Patient fears of optimising and intensifying insulin treatment
Perceptions of Control study: n = 620 UK patients with type 2 diabetes
Reason for apprehension with HCP recommendation
% patients
Fear of weight gain
45%
Perception of ‘getting sicker’
44%
Fear of hypoglycaemia
41%
Unhappy with more injections
Concern that is ‘too complicated’
37%
Speaker notes
Patients and physicians both express concerns and apprehensions about optimising and intensifying insulin.
The Perceptions of Control study
Physican selection criteria -
Had to see a minimum of 10% of T2D patients treated with basal insulin only (with or without OADs)
Must be the primary decision maker for changing insulin therapy for their T2D patients
Minimum 2 years expertise in diabetes treatment
Mix of GPs & Diabetologists
Patient selection criteria -
In order to complete the survey, patients were required to contact their physician to obtain their most recent HbA1C value recorded and the date it was taken.
Patients with uncontrolled diabetes (HbA1C > 8.0%)
Willingness to progress to 1x additional bolus injection
% patients
Willing
43%
Somewhat willing
37%
Not at all willing
18%
Brod M et al. P st EASD Annual Meeting 2015

47. Physician fears of optimising and intensifying insulin treatment
Perceptions of Control study: n = 100 UK physicians
Reason for apprehension
% HCPs
Expectation that patient will refuse
62%
General fear of hypoglycaemia
46%
Fear of patient’s workplace hypoglycaemia
54%
Patient’s mental state
48%
Patient’s cognitive abilities
Unconvinced patient will comply
41%
Speaker notes
Patients and physicians both express concerns and apprehensions about optimising and intensifying insulin.
The Perceptions of Control study
Physican selection criteria -
Had to see a minimum of 10% of T2D patients treated with basal insulin only (with or without OADs)
Must be the primary decision maker for changing insulin therapy for their T2D patients
Minimum 2 years expertise in diabetes treatment
Mix of GPs & Diabetologists
Patient selection criteria -
In order to complete the survey, patients were required to contact their physician to obtain their most recent HbA1C value recorded and the date it was taken.
Patients with uncontrolled diabetes (HbA1C > 8.0%)
Brod M et al. P st EASD Annual Meeting 2015

48. Summary
Type 2 diabetes will ultimately require the initiation of insulin- replacement therapy.
Initiating people with type 2 diabetes onto basal-insulin therapy is a clinically proven strategy.
For patients failing on OADs, the point of initiation is the subject of considerable clinical inertia.
Once initiated, basal-insulin optimisation and intensification is not actively pursued despite evidence of continued poor glycaemic control.
Clinical inertia is a feature both of HCP attitudes and patient fears.
Speaker notes
Self evident, summary slide

49. ABASAGLAR®▼ CARTRIDGE AND KWIKPEN™ PRESCRIBING INFORMATION ABASAGLAR IS INSULIN GLARGINE (human insulin analogue)
Presentation Abasaglar is a clear, colourless, sterile solution of 100 units/ml (equivalent to 3.64mg) insulin glargine (rDNA origin), available as either 3ml cartridge or 3ml KwikPen. Each cartridge/pen contains 300 units of insulin glargine in 3ml solution. Uses Treatment of diabetes mellitus in adults, adolescents, and children aged 2 years and above. Dosage and Administration The dose regimen (dose and timing) should be individually adjusted. In patients with Type 2 diabetes mellitus, Abasaglar can also been given together with orally active antidiabetic medication. Abasaglar has a prolonged duration of action, and should be administered once daily at any time, but at the same time each day. It should only be given by subcutaneous injection and should not be administered intravenously. Injection sites must be rotated within a given injection area from one injection to the next. Abasaglar must not be mixed with any other insulin or diluted. When changing from another intermediate or long-acting insulin treatment regimen to Abasaglar, a change of the dose of the basal insulin may be required and the concomitant antidiabetic treatment may need to be adjusted (dose and timing of additional regular insulins or fast-acting insulin analogues, or the dose of oral antidiabetic medicinal products). Contra-indications Hypersensitivity to insulin glargine or any of the excipients. Warnings and Special Precautions Abasaglar is not the insulin of choice for the treatment of diabetic ketoacidosis. In case of insufficient glucose control, or tendency to hyper- or hypoglycaemic episodes, other relevant factors must be reviewed before dose adjustment is considered. Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand, type, origin, and/or method of manufacture may result in the need for a change in dose. In rare cases, insulin antibodies may necessitate dose adjustment. The time of occurrence of hypoglycaemia may change when the insulin regimen is .
changed, depending on the action profile of the insulins used. Caution and intensified glucose monitoring are advised in patients for whom hypoglycaemia might be of particular clinical relevance. Patients should be aware that warning symptoms of hypoglycaemia may be changed, less pronounced, or absent in certain circumstances, including: markedly improved glycaemic control; when hypoglycaemia develops gradually; in the elderly; after transfer from animal to human insulin; autonomic neuropathy; long history of diabetes; psychiatric illness; use of certain medications such as beta-blockers. This may result in severe hypoglycaemia. The prolonged effect of insulin glargine may delay recovery from hypoglycaemia. If HbA1c is low, consider possibility of recurrent, unrecognised hypoglycaemia. Adherence of the patient to the dose and dietary regimen, correct insulin administration, and awareness of hypoglycaemia symptoms are essential to reduce risk of hypoglycaemia. Factors increasing risk of hypoglycaemia require particularly close monitoring and may necessitate dose adjustment. Intercurrent illness requires intensified monitoring. Testing for ketones and dose adjustment may be necessary. Patients with Type 1 diabetes must continue to consume at least small amounts of carbohydrate and must never omit insulin entirely. The cartridges should only be used in a pen recommended for the use with Lilly insulin cartridges. The insulin label must always be checked before each injection to avoid medication errors. Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin. If the combination is used, patients should be observed for signs and symptoms of heart failure and pioglitazone discontinued if any deterioration occurs. Pregnancy and Lactation No clinical data from controlled studies are available. Data from >1,000 pregnancy outcomes indicate no specific adverse effects of insulin glargine on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Abasaglar may be considered during pregnancy, if .
necessary. Insulin requirements may decrease during the first trimester and generally increase during the second and third trimesters. Immediately after delivery, insulin requirements decline rapidly. Careful monitoring of glucose control is essential. Driving, etc The patient’s ability to concentrate and react may be impaired as a result of hypo- or hyperglycaemia, or visual impairment. This may constitute a risk in situations where these abilities are of special importance (eg, driving a car or operating machines). Undesirable Effects Hypoglycaemia is very common. Injection site reactions and lipohypertrophy are common. Immediate-type allergic reactions are rare, but may be life-threatening. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at Legal Category POM Marketing Authorisation Numbers EU/1/14/944/003, EU/1/14/944/007 Basic NHS Cost £ X 3ml cartridges, £ X 3ml KwikPens Date of Preparation or Last Review May 2015 Full Prescribing Information is Available From Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Telephone: Basingstoke (01256) Website: ABASAGLAR® (insulin glargine) is a registered trademark of Eli Lilly and Company. KWIKPEN™ is a trademark of Eli Lilly and Company.
Adverse events should be reported. Reporting forms and further information can be found at:
Adverse events and product complaints should also be reported to Lilly: please call Lilly UK on