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Scientific slides: Introduction to Type 2 diabetes and the unmet need
Date of preparation: Apri l 2014 150515
Developed with the guidance and approval of an
independent international editorial committee
Content guide
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i
Expert sound bite
• All graphs have been created in PowerPoint to enable easy amends and translation
• HbA1c values and appropriate graphs include both
DCCT (%) and IFFC (mmol/mol) units. Please delete where not appropriate for your
market
DCCT, Diabetes Control and Complications Trial; IFFC, International Federation of Clinical Chemistry and Laboratory Medicine.
Executive summary
• This slide deck covers the following topics and contains speaker
notes to assist presentation:
1. Introduction to Type 2 diabetes
• Unmet needs and barriers to treatment
– Epidemiology of Type 2 diabetes
– Barriers to treatment (weight gain, hypoglycaemia, adherence to treatment)
• The Type 2 diabetes treatment pathway and individualised care
– The place of GLP-1 receptor agonists and insulin in the treatment pathway
2. GLP-1 receptor agonists and the discovery of exenatide
• GLP-1 mechanism of action and the incretin effect
• The discovery of exenatide, the first GLP-1 receptor agonist
Introduction to Type 2 diabetes: Unmet
needs and barriers to treatment
<Insert speaker name>
The unmet needs in the management of
Type 2 diabetes
Approximately 53 million adults suffer from diabetes in Europe
• 8.1% of the adult population in Europe suffer from diabetes
• By 2030, the prevalence of diabetes in Europe is forecast to rise to 9.5% of the adult
population
Prevalence* of diabetes (20–79 years) in Europe, 2011
Adapted from The International Diabetes Federation. Diabetes Atlas, 5th edition (2011). Available at: http://www.idf.org./diabetesatlas/5e/europe. Last accessed August 2013.
6
The growing burden of Type 2 diabetes
i
Expert sound bite
• Placeholder for video 1Ai. Dr Javier Francisco Ampudia Blasco: The growing
burden of Type 2 diabetes
7
Despite advances in treatment, a significant proportion of patients
with Type 2 diabetes still fail to reach target HbA1c levels
PANORAMA study (2009)2
Percentage of patients not achieving target HbA1c level: <7.0% (<53 mmol/mol)
Patients not controlled (%)
100
90
80
70
60
50
40
30
20
10
0
Nine EU
countries
(n=5817)
UK
(n=501)
France
(n=759)
Germany
(n=808)
Italy
(n=752)
Adapted from De Pablos-Velasco P, et al. Clin Endocrinol (Oxf) 2012; Epub ahead of print.
Spain
(n=752)
Belgium Netherlands Greece
(n=611)
(n=659)
(n=375)
Turkey
(n=600)
Type 2 diabetes as a progressive disease and its increasing unmet
need
i
Expert sound bite
• Placeholder for video 1Aii. Professor Stephan Jacob: Type 2 diabetes as a
progressive disease and its increasing unmet need
9
Traditional approaches to Type 2 diabetes management often have
limited success
• Traditionally, Type 2 diabetes has been managed by a stepwise, conservative
approach where regimens are changed only when symptoms become apparent
– In the majority of cases, this approach does not lead to sustained glycaemic control
Diet
+ drug
+ drug
+ basal
insulin
Complex
insulin
regimen
10
HbA1c levels (%)
9
70
8
60
7
6
50
Diagnosis
+5 years
Duration of diabetes
Adapted from Campbell IW. Br J Cardiol 2000;7:625–31.
+10 years
+15 years
HbA1c levels (mmol/mol)
80
Early, intensive interventions can support long-term glycaemic
control
• Adoption of an intensive, goal-focused strategy from diagnosis can improve long-term
glycaemic control in Type 2 diabetes
– Any combination regimen should be well tolerated as well as efficacious, to promote adherence
Diet
+ drug
+ drug
+ basal
insulin
Complex
insulin
regimen
10
HbA1c levels (%)
9
70
8
60
7
6
50
Diagnosis
+5 years
Duration of diabetes
Adapted from Campbell IW. Br J Cardiol 2000;7:625–31.
+10 years
+15 years
HbA1c levels (mmol/mol)
80
Managing Type 2 diabetes through early interventions
i
Expert sound bite
• Placeholder for video 1Aiii. Professor Kamlesh Khunti: Managing Type 2
diabetes through early interventions
12
The barriers to effective treatment of Type 2 diabetes
• Many barriers to effective treatment of Type 2 diabetes have been identified.
These include:
1. Weight gain, either from lifestyle or antidiabetic medication1
2. Rates and fear of hypoglycaemia, due to use of certain classes of antidiabetic
therapies2
3. Poor adherence to therapy3
4. Clinical inertia around the progressive nature of Type 2 diabetes and eventual
requirement for insulin4,5
1. UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65; 2. Amiel SA, et al. Diabet Med 2008;25:245–54; 3. Guisasola AF. Diabetes Obes Metab
2008;10(Suppl. 1):25–32; 4. Weyer C, et al. J Clin Invest 1999;104:787–94; 5. Khunti K, et al. Diabetes Care 2013;36:3411–7.
Raising awareness of diabetes and its associated risk factors
i
Expert sound bite
• Placeholder for video 1Aiv. Paul Dromgoole: Raising awareness of diabetes
and its associated risk factors
14
Diabetes and obesity are closely interlinked
Relationship between BMI and risk of Type 2 diabetes
Age-adjusted relative risk
for Type 2 diabetes
100
Normal weight
Overweight
Obese
75
Women
50
Men
25
0
<23
<23–23.9 <24–24.9 <25–26.9 <27–28.9 <29–30.9 <31–32.9 <33–34.9
≥35
BMI (kg/m2)
*Results are from two different studies. The first study is from a cohort of 27,983 US male health professionals, 40–75 years of age in 1986 who completed biennial
questionnaires sent out in 1986, 1988, 1990 and 1992 (follow-up: 1987–1992). The second study is from a cohort of 114,281 US female registered nurses, 30–55 years of
age in 1976 who completed questionnaires (follow-up: 1976–1990).
BMI, body mass index.
Adapted from: 1. Chan J, et al. Diabetes Care 1994;17:961–9; 2. Colditz GA, et al. Ann Intern Med 1995;122:481–6.
Disease progression is associated with weight change
Baseline patient characteristics associated with diabetes progression* over
the subsequent year (n=705)
Non-progressors
(n=505)
Progressors
(n=200)
p value
Baseline weight (kg)
84.9 ± 19.5
88.3 ± 24.4
0.16
Baseline BMI (kg/m2)
32 ± 6.9
32.3 ± 9.3
0.78
Change in weight (kg)
–0.9 ± 7.5
0.2 ± 7.2
0.17
Baseline SBP (mmHg)
129.3 ± 17.6
127.9 ± 16.5
0.36
Baseline DBP (mmHg)
74.7 ± 11.3
73.8 ± 10.9
0.36
Clinical characteristics
*HbA1c levels ≥7% or initiation of antidiabetic agent in patients with HbA1c <7.0% (<53.0 mmol/mol) and not on glucose-lowering medications at baseline.
BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.
Pani LN, et al. Diabetes Care 2008;31:386–90.
In patients with Type 2 diabetes, weight loss provides
multiple benefits: The Look AHEAD study
Odds ratio for the percentage of the Look AHEAD patient cohort achieving
clinically meaningful changes in CVD risk factors at 1 year after a weight loss
of ≥5% to <10% (n=1000/5145)
Clinical criteria
0.05%
in HbA1c
Odds ratio
95% CI
3.52
2.81, 4.40
5 mmHg
in SBP
1.56
1.27, 1.91
5 mmHg
in DBP
1.48
1.20, 1.82
5 mg/dL
in HDL cholesterol
1.69
1.37, 2.07
This study was an observational analysis of participants in the Look AHEAD study conducted at 16 US sites in 5,145 participants
(40.5% male, 37% from ethnic/racial minorities).
40 mg/dL
in triglycerides
2.20
1.71, 2.83
AHEAD, Action for Health Diabetes; CI, confidence interval; CVD, cardiovascular disease; DBP, diastolic blood pressure; HDL, high-density lipoprotein,
SBP, systolic blood pressure.
Wing RG, et al. Diabetes Care 2011;34:1481–6.
Many current therapies are associated with hypoglycaemia
• During the UKPDS, self-reported hypoglycaemic symptoms were graded using a
four-point scale:
1.
2.
3.
4.
Transitory symptoms not affecting normal activity
Temporarily incapacitated but patient able to control symptoms without help
Incapacitated and required assistance to control symptoms
Required medical attention or glucagon injection
Therapy
n*
Annual percentage of patients reporting at least
one hypoglycaemic episode, % (95% CI)
Grades 1–4
Grades 2–4
Diet
756
0.8 (0.6 to 1.0)
0.1 (0.1 to 0.2)
SU
1418
7.9 (5.1 to 11.9)
1.2 (0.4 to 3.4)
Metformin
290
1.7 (1.0 to 3.0)
0.3 (0.1 to 1.1)
Basal insulin
1036
21.2 (14.6 to 29.8)
3.8 (1.2 to 11.1)
38
32.6 (21.8 to 45.6)
5.5 (2.0 to 14.0)
Basal + prandial insulin
*Patients taking assigned therapy over 6 years’ follow-up.
CI, confidence interval; SU, sulphonylurea; UKPDS, UK Prospective Diabetes Study.
Wright AD, et al. J Diabetes Complications 2006;20:395–401.
Severe hypoglycaemia is associated with poor CV outcomes and
mortality
ADVANCE study
Events
No. of patients with events (%)
Severe
No severe
hypoglycaemia
hypoglycaemia
(n=231)
(n=10,909)
Major macrovascular events
Unadjusted model
Adjusted model
33 (15.9)
Major microvascular events
Unadjusted model
Adjusted model
24 (11.5)
Death from any cause
Unadjusted model
Adjusted model
45 (19.5)
Death from CV cause
Unadjusted model
Adjusted model
22 (9.5)
Death from non-CV cause
Unadjusted model
Adjusted model
23 (10.0)
HR (95% CI)
1114 (10.2)
4.05 (2.86 to 5.74)
3.53 (2.41 to 5.17)
1107 (10.1)
2.39 (1.60 to 3.59)
2.19 (1.40 to 3.45)
986 (9.0)
4.86 (3.60 to 6.57)
3.27 (2.29 to 4.65)
520 (4.8)
4.87 (3.17 to 7.49)
3.79 (2.36 to 6.08)
466 (4.3)
4.82 (3.16 to 7.35)
2.80 (1.64 to 4.79)
The HR represents the risk of an adverse clinical outcome or death among patients reporting severe hypoglycaemia compared with those not reporting severe hypoglycaemia.
CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio.
Zoungas S, et al. N Engl J Med 2010;363:1410–8.
The costs of severe hypoglycaemia
• The cost implications of severe hypoglycaemia, both direct hospital costs and indirect
costs due to inability to work, are considerable1,2
Cost per severe hypoglycaemic event (year 2007)2
Average patient with
Type 2 diabetes
Patient requiring
hospitalisation
Germany
€533
€3023
Spain
€691
€1404
UK
€537
€1314
Country
• There is evidence to suggest that people with Type 2 diabetes lose, on average,
•
3 productive days following a severe hypoglycaemic attack1
Inpatient costs are consistently higher than outpatient costs, due to increased medical
care for diabetes-related complications3
1. Amiel SA, et al. Diabet Med 2008;25:245–54; 2. Hammer M, et al. J Med Econ 2009;12:281–90; 3. Kanavos P, et al. 2012. Available at:
http://www.lse.ac.uk/lsehealthandsocialcare/research/lsehealth/mtrg/lsediabetesreport26jan2012.pdf. Last accessed June 2013.
Quality of life issues: Patient fear regarding hypoglycaemia
• Fear of hypoglycaemia:1
–
–
–
–
Is an additional psychological burden on patients
May limit the aggressiveness of drug therapy
Can decrease adherence to treatment recommendations
May reduce compliance with therapy
• Fear of hypoglycaemia can influence:
– Patient health outcomes (prevention or delay of diabetes-related complications)2
– Post-episode lifestyle changes2
• A severe hypoglycaemic event can increase fear of hypoglycaemia in the
future3
1. Leiter LA, et al. Can J Diab 2005;29:186–92; 2. Davis S, et al. J Diab Comp 2004;18:60–8; 3. Currie CJ, et al. Curr Med Res Opin 2006;22:1523–34.
Patients making lifestyle changes following a
hypoglycaemic episode (%)
Hypoglycaemia is a cause of lifestyle modifications in patients with
Type 2 diabetes
100
Mild/moderate hypoglycaemia
90
Severe hypoglycaemia
84.2
80
70
62.9 63.2
57.9
60
50
57.9
43.3
40
30
32
29.9
26.3
15.8
20
10
9.4
14.4
10.3
9.3
0
Modified insulin Ate extra food Increased fear
Additional
Asked
Went home
dose
of future hypo concerns about someone to
from
driving
check on them work/activities
Stayed home
the next day
Graph shows patients (n=202) who ‘sometimes’ or ‘always’ made lifestyle changes within 24 hours of a hypoglycaemic episode, in a self-administered questionnaire.
Mild/moderate hypoglycaemia, plasma glucose ≤4.0 mol/L; severe hypoglycaemia, plasma glucose <2.8 mmol/L and requiring assistance.
Adapted from Leiter LA, et al. Can J Diab 2005;29:186–92.
The requirement for more intelligent compounds such as the
incretin-based agents
i
Expert sound bite
• Placeholder for video 1Av. Professor Stephan Jacob: The requirement for
more intelligent compounds such as the incretin-based agents
23
Many patients with diabetes do not adhere to their treatment
• Poor patient adherence to treatment is an important barrier to glycaemic control1
• Retrospective studies in people with Type 2 diabetes reported adherence rates of
Persistent patients (%)
•
36–93% for oral agents and 62–64% for insulin1
Therapy persistence has been shown to decrease with time, and with polytherapy
compared with monotherapy2
100
Metformin monotherapy
SU monotherapy
Metformin + SU polytherapy
80
60
40
20
0
0
8
16
24
32
40
48
Week
56
Figure from Dailey et al.2
SU, sulphonylurea.
1. Cramer JA. Diabetes Care 2004;27:1218–24; 2. Dailey G, et al. J Int Med Res 2002;30:71–9.
64
72
80
88
96
Clinical inertia can lead to poor glycaemic control in patients with
Type 2 diabetes
• Clinical inertia is the failure to intensify treatment in a timely manner
• There is a delay in intensifying treatment in people with Type 2 diabetes with
poor glycaemic control, which leads to prolonged periods of hyperglycaemia
– Patients may remain in poor glycaemic control for over 7 years before
intensification of treatment with insulin
– In patients taking 1 or 2 OADs, median time from initiation of treatment to
intensification with an additional OAD exceeded the study’s maximum follow-up
time of 7.3–7.3 years
Treatment intensification was defined as either addition of further OAD prescription without changes in current OAD prescription, or initiation of insulin irrespective of changes
in OAD regimen.
OAD, oral antidiabetic drug.
Khunti K, et al. Diabetes Care 2013;36:3411–7.
Requirements for aggressive antidiabetic treatment beyond diet
and exercise
i
Expert sound bite
• Placeholder for video 1Avi. Professor Kamlesh Khunti: Requirements for
aggressive antidiabetic treatment beyond diet and exercise
26
The Type 2 diabetes treatment pathway and
individualised care
ADA/EASD 2012 position statement on the management of
Type 2 diabetes
“An approach to providing care that is respectful of and responsive to individual
patient preferences, needs, and values and ensuring that patient values guide all
clinical decisions.” – ADA/EASD position statement 2012
• Key points:
– Glycaemic targets and glucose-lowering therapies must be individualised
•
HbA1c <7% (<53 mmol/mol) for most patients
•
More stringent (e.g. 6.0–6.5% [42.1–47.5 mmol/mol]) and less stringent HbA1c targets might be considered
in selected patients
– Diet, exercise, and education remain key
– All treatment decisions should be made in conjunction with the patient, focusing on his/her
preferences, needs and values
– Comprehensive CV risk reduction must be a major focus of therapy
– Additional considerations include: Age, weight, sex/racial/ethnic/genetic differences and
comorbidities
ADA, American Diabetes Association; CV, cardiovascular; EASD, European Association for the Study of Diabetes.
Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.
Avoiding side effects of treatment with antidiabetic agents
i
Expert sound bite
• Placeholder for video 1Avii. Paul Dromgoole: Avoiding side effects of
treatment with antidiabetic agents
29
Individualisation of treatment goals is key
Approach to management of hyperglycaemia
More stringent
Less stringent
Risks potentially associated with
hypoglycaemia and other adverse events
Low
High
Disease duration
Newly diagnosed
Long-standing
Life expectancy
Long
Short
Important comorbidities
Absent
Few/mild
Severe
Established vascular
complications
Absent
Few/mild
Severe
Resources,
support system
Readily available
Limited
Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.
The figure depicts elements to
consider when making decisions
about HbA1c targets for specific
patients.
The scale is not designed to be
applied rigidly but to serve as a
broad framework to assist in
determining glycaemic targets.
Antihyperglycaemic therapy in Type 2 diabetes
• Metformin is the most commonly used first-line drug for treating Type 2 diabetes1
• After metformin, there are a number of treatment options available1
– Combination therapy is reasonable, aiming to minimise side effects where possible
Considerations when prescribing commonly-used non-insulin antidiabetic agents2
MET
DPP4-i
GLP-1 RA
SGLT2-i
SU
TZD
Hypoglycaemia
risk
Neutral
Neutral
Neutral
Neutral
Moderate /
severe
Neutral
Weight
Slight loss
Neutral
Loss
Loss
Gain
Gain
Renal
impairment
Contraindicated
Stage 3B–5
Dose
adjustment
required†
Exenatide
contraindicated
CrCl <30
Infections
More hypo risk
May worsen
fluid retention
GI Sx
Moderate
Neutral
Moderate
Neutral
Neutral
Neutral
• Recent guidelines position GLP-1 receptor agonists as add-on to metformin or
multiple OADs in the treatment pathway1
• Ultimately, many patients will require insulin therapy1
Table adapted from Garber AJ, et al. 2013.2
*In patients intolerant to metformin or for whom metformin is contraindicated. †Except linagliptin.
CrCl, creatinine clearance; DPP4-i, dipeptidyl peptidase-4 inhibitor; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; MET, metformin; OAD, oral antidiabetic drug;
SGLT2-i, sodium-glucose co-transporter 2 inhibitor; SU, sulphonylurea; Sx, side effects; TZD, thiazolidinedione.
Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79; 2. Garber AJ, et al. Endocr Pract 2013;19:327–36.
Complexity of insulin regimens increases as Type 2 diabetes
progresses
Non-insulin regimens
Treatment
convenience
Number of Regimen
injections complexity
Basal insulin only
(usually with oral agents)
Low
1
Pre-mixed insulin
twice daily
2
3+
High
Basal insulin
+1 (mealtime) rapid-acting
insulin injection
Basal insulin
+ ≥2 (mealtime)
rapid-acting insulin
injections
Less flexible
Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.
Adapted from: Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.
More
convenient
Less
convenient
More flexible Flexibility
Use of GLP-1 receptor agonists early in the treatment pathway
i
Expert sound bite
• Placeholder for video 1Aviii. Paul Dromgoole: Use of GLP-1 receptor
agonists early in the treatment pathway
33
Comparison of GLP-1 receptor agonists with insulin
• GLP-1 receptor agonists offer a different suite of advantages and
disadvantages for consideration when individualising care
GLP-1 receptor agonist Insulin
Hypoglycaemia risk
Low
High
Weight change
Loss
Gain
Major side effect(s)
Gastrointestinal
Hypoglycaemia
Daily titration required?


Additional blood glucose
monitoring required?


Costs
High
Variable
GLP-1, glucagon-like peptide-1.
Adapted from Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.
Advantages of new antidiabetic treatments
i
Expert sound bite
• Placeholder for video 1Aix. Paul Dromgoole: Advantages of new antidiabetic
treatments
35
The 4-T study: Increasing the basal insulin dose does not always
result in further HbA1c reductions
Mean changes in basal insulin dose
Mean changes in HbA1c
Basal insulin
Biphasic insulin
Prandial insulin
75
1.5
70
HbA1c (%)
65
60
55
7
50
45
6
0
0
0
0.5
1
1.5
2
2.5
3
Years since randomisation
4-T, Treating to Target in Type 2 diabetes.
Adapted from Holman R, et al. N Engl J Med 2009;361:1736–47.
HbA1c (mmol/mol)
8
Daily insulin dose (IU/kg)
9
Basal insulin
Biphasic insulin
Prandial insulin
1.0
0.5
0.0
0
0.5
1
1.5
2
2.5
Years since randomisation
3
Basal insulin is sometimes not sufficient to achieve glycaemic
control, even when titrated properly
Percentage of patients who did not reach
HbA1c ≤7% (≤53 mmol/mol) after 6 months1
Percentage of patients achieving
HbA1c ≤7% (≤53 mmol/mol) at 1 year2
100
80
60
42.0%
42.7%
40
20
Percentage of patients
at target HbA1c (%)
Percentage of patients
at target HbA1c(%)
100
0
80
60
40
27.8%
20
0
Insulin glargine
Insulin determir
NPH
Percentage of patients who did not reach
HbA1c ≤7.0% (≤53 mmol/mol) after 6 months of
basal insulin therapy with forced titration to target
FPG ≤5.5 mmol/L (100 mg/dL)1
Percentage of patients at or below target HbA1c
after 1 year of basal insulin therapy2
FPG, fasting plasma glucose; NPH, neutral protamine Hagedorn.
1. Riddle MC, et al. Diabetes Care 2003;26:3080–6; 2. Holman R, et al. N Engl J Med 2007;357:1716–30.
Discussing potential use of injectable agents with patients for
treatment of Type 2 diabetes
i
Expert sound bite
• Placeholder for video 1Ax. Paul Dromgoole: Discussing potential use of
injectable agents with patients for treatment of Type 2 diabetes
38
Reasons why patients may be unwilling to begin insulin therapy
Unwilling to begin
insulin (%)
Willing to begin
insulin* (%)
Significantly
different?
Low self-efficacy
58.1
39.7

Restrictiveness
56.1
41.6

Personal failure
55.0
33.6

Permanence
53.1
42.6

Anticipated pain
50.8
30.2

Problematic hypoglycaemia
49.3
37.9

Severity of illness
46.7
35.4

Lack of fairness
41.5
21.9

Expected harm
16.7
8.0

Data from n=3833 attendees at nine public sessions on ‘Taking control of your diabetes’. 1267 questionnaires were returned; 708 individuals had Type 2 diabetes and were
not receiving insulin.
*Percentages of patients responding that they would be slightly willing, 24.8%; moderately willing, 23.3%; very willing, 24.4%.
Polonsky WH, et al. Diabetes Care 2005 28:2543–5.
Patient beliefs and ability to engage with treatment
i
Expert sound bite
• Placeholder for video 1Axi. Paul Dromgoole: Patient beliefs and ability to
engage with treatment
40
Changing patient and healthcare professional perceptions of
injectable agents
i
Expert sound bite
• Placeholder for video 1Axii. Paul Dromgoole: Changing patient and
healthcare professional perceptions of injectable agents
41
Halting Type 2 diabetes disease progression by physiological
mechanisms
i
Expert sound bite
• Placeholder for video 1Axiii. Professor Stephan Jacob: Halting Type 2
diabetes disease progression by physiological mechanisms
42
Summary: Type 2 diabetes and individualised care
• There are a number of unmet needs in Type 2 diabetes, which are in part fuelled by
barriers to treatment such as:
–
–
–
–
Weight gain
Hypoglycaemia and patient fear of hypoglycaemia
The progressive nature of the disease and patients’ unwillingness to start insulin
Poor adherence to medication
• An individualised approach to diabetes care may help to overcome some barriers to
treatment
Inzucchi SE, et al. Diabetes Care 2012;35:1364–79.