Transcript Document

Patient adherence in type 2 diabetes:
What’s the issue and how to address it
Anthony Barnett
University of Birmingham and Heart of England
NHS Foundation Trust, UK
Definition of compliance and persistence
Compliance: extent to which a patient acts in accordance with the prescribed
interval and dose of dosing regimen
Persistence: accumulation of time from initiation to discontinuation of therapy
Adherence: encompasses both
Prescribed regimen for 12 months
Fully compliant for 12 months
Fully persistent for 12 months
Partially compliant
Non-persistent (stopped therapy before 12 months)
Non-compliant and non-persistent
Non-acceptance (does not start therapy)
So what really happens when you fill a prescription?
PERSISTENCE
Persistent patients (%)
120
Metformin monotherapy
Sulphonylurea monotherapy
M+SU polytherapy
100
80
60
40
20
0
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104
Weeks of therapy
4,033
11,234
Persistence
(in days)b
183.8
183.1
142.7
141.8
Persistence
rate (%)c
51.06
50.86
661
915
2983
158
111.1
296.7
274.3
121.9
117.4
285.1
276.5
186.9
30.86
41.21
38.10
16.93
Study period
Study groupa
n
1 year
(360 days)
Metformin (M)
Sulphonylurea
(SU)
M+SU
Metformin
Sulphonylurea
M+SU
2 YEARS
(720 days)
US population 2002. J Int Med Res. 2002;30:71.
SD
So what really happens when you fill a prescription?
COMPLIANCE
Patients remaining
compliant to therapy (%)
100
80
60
65.06
64.64
40
63.07
60.54
44.42
35.76
20
0
1 Year (360 days)
Metformin
Study period
Study groupa
1 year
(360 days)
Metformin (M)
Sulphonylurea
(SU)
M+SU
Metformin
Sulphonylurea
M+SU
2 YEARS
(720 days)
US population 2002. J Int Med Res. 2002;30:71.
2 Years (720 days)
Sulphonylurea
Metformin + Sulphonylurea
Compliance
Persistence
n
SD
(in days)b
rate (%)c
4033
234.2
110.8
65.06
11,234
232.7
113.6
64.64
661
915
2983
158
159.9
454.1
435.9
257.5
115.3
232.2
232.6
228.2
44.42
63.07
60.54
35.76
Diabetes Audit and Research in Tayside Study (DARTS)
• Study population
– All people with Type 2 Diabetes living in Tayside, Scotland
(~420,000)
– First prescription for oral anti-diabetes drug from 1 January 1993
onward
– Follow-up to 31 December 1995 with at least 12 months of
prescriptions
Total time drug prescribed
= Adherence index
Total time of follow-up
Donnan PT et al. Diabet Med. 2002;19:279-284.
Adherence index by type of therapy
Monotherapy
Sulphonylurea
Metformin
31
34
Polytherapy
Sulphonylurea
Metformin
19
13
Donnan PT et al. Diabet Med. 2002;19:279-284.
Once the patient has ACCEPTED treatment,
is everything fine?
Retrospective, cohort study of
community pharmacy records (N=2,325)
Continuous hypertensive users (%)
100
90
80
70
60
50
Men
Women
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Years after first prescription
Van Wijk et al. J Hypertens. 2005;23:2101-2107.
9
10
Does it matter?
Lessons from hypertension: improved outcome
All-cause hospitalisation risk (%)
40
44
39
30
36
30
20
27
10
0
1-19
20-39
40-59
Level of compliance (%)
Sokol et al. Med Care. 2005;43:521-530.
60-79
80-100
Does it matter?
Lessons from hypertension: improved BP control
Patients with BP control* (%)
*
40
42%
30
33%
32%
Medium
(50%–79%)
Low
(< 50%)
20
10
0
High
(≥ 80%)
Compliance (measured using MPR)
Odds ratio = 1.45.
*P = 0.026 (controlling for age, gender, and co-morbidities).
Bramley et al. J Manag Care Pharm. 2006;12:239-245.
BUT for type 2 diabetes it can be difficult
•
•
•
•
Progressive disease
Multi-system disease with co-morbidities—polypharmacy!
Complex guidelines
Unmet needs of pharmacotherapies
Progressively declining beta cell function in T2D
‘waiting for failure’
Insulin ±oral
Dual drugs for lowering
Lifestyle Monotherapy therapy blood glucose
100
ß-cell function (%)
10
9
7
6
HbA1c
5
ß-cell function
0
0
>15
0
Time (years)
Adapted from: Heine RJ et al. BMJ. 2006;333:1200-1204.
HbA1c (%)
8
The treatment complexity in type 2 diabetes drives
non-adherence to management strategies
Medication for Complex Diabetes
A 42-year-old woman’s regimen for
treating complex diabetes includes…
• At least 15 types of oral medication
• 2 over-the-counter products
• 7 to 10 injections
• 4 blood tests
…per day, costing over $1,800 a month
retail
Source: Dr. John Buse, The New York Times
Current treatment paradigms for type 2 diabetes
are not “user-friendly”
Mild to moderate hyperglycaemia (HbA1C <9.0%)
Non-overweight
(BMI < 25 kg/m2)
Overweight
(BMI ≥ 25 kg/m2)
L I F E S T Y L E
Biguanide alone or in
combination with 1 of:
•insulin sensitizer
•insulin secretagogue
•insulin
•alpha-glucosidase
inhibitor
If not at target
Marked hyperglycaemia (HbA1C ≥9.0%)
1 or 2 anti-hyperglycaemic
agents from different classes
•biguanide
•insulin sensitizer
•insulin secretagogue
•insulin
•alpha-glucosidase
inhibitor
If not at target
Add a drug from a different class
or use insulin alone or in combination with:
2 anti-hyperglycaemic agents Basal and/or
from different classes
pre-prandial insulin
•biguanide
•insulin sensitizer
•insulin secretagogue
•insulin
•alpha-glucosidase
inhibitor
If not at target
Add an oral
anti-hyperglycaemic agent
from a different
class or insulin
•biguanide
•insulin secretagogue
•insulin sensitizer
•alpha-glucosidase
inhibitor
Timely adjustments to and/or additions of oral anti-hyperglycaemic agents
and/or insulin should be made to attain target HbA1C within 6 to 12 months
If not at target
Intensify insulin
regimen or add
•biguanide
•insulin secretagogue
•insulin sensitiser
•alpha-glucosidase
inhibitor
Unmet patient & physician needs in the treatment
of type 2 diabetes in Europe
Physicians’ Need for Improvement*
Percent
Patients’ Need for Improvement†
Percent
40
40
35
35
30
30
GI side effect profile
25
25
Weight loss
20
Preserves beta cell function
15
Weight loss
20
HbA1c
10
Hypoglycaemia
15
Ease of Use
10
Cost
5
HbA1c
5
0
0
0
10
20
30 40
50 60 70 80 90 100
Reasons for choice*
Percent
0
5
10
15
20
Reasons for choice†
Percent
*Physicians were asked to indicate key areas. †Patients were asked to choose top three most important areas.
25
30
RESULT:
Patients often fail to achieve glycaemic targets
China
(CODIC-2)1
HbA1c < 7.5%
32%
Europe
Latin America
(CODE-2)5
HbA1c < 6.5%
(DEAL)3
HbA1c <7%
68%
31%
43%
57%
Canada
(DICE)2
HbA1c < 7%
US
69%
(NHANES)4
HbA1c < 7%
37%
51%
49%
63%
Achieving glycaemic target
Failed to achieve glycaemic target
1. Xingbao C. Chinese Health Economics. 2003. Ling T. China Diabetic Journal. 2003. 2. Harris SB et al. Diabetes Res
Clin Pract. 2005;70:90-97. 3. Lopez Stewart G et al. Rev Panam Salud Publica. 2007;22:12-20. 4. Saydah SH et al.
JAMA. 2004;291:335-342. 5. Liebl A et al. Diabetologia. 2002;45:S23-S28.
Most common factors related to non-adherence in
patients with type 2 diabetes
11%
8%
Others*
Cost
23%
Difficulty in
remembering
doses
Side effects
*Number of prescribed medications, patient characteristics
N=128 patients with Type 2 Diabetes.
Grant RW et al. Diabetes Care. 2003;26:1408-1412.
58%
Only 23% of patients
who had side effects
reported the problems to
their primary care physician
Adherence to oral anti-diabetes agents
Literature search to determine extent of omitted oral anti-diabetes agents
Percentage of patients remaining
compliant to therapy
100
90
80
70
79.1
60
65.6
50
40
30
38.1
20
10
0
Once-daily
regimens
Cramer J. Diabetes Care. 2004;27:1218-1224.
Twice-daily
regimens
Three times
daily regimens
Most current therapies promote weight gain
UKPDS: up to 8 kg in 12 years
ADOPT: up to 4.8 kg in 5 years
8
Insulin (n=409)
6
96
Weight (kg)
Change in weight (kg)
7
5
Glibenclamide (n=277)
4
3
2
92
Glibenclamide (n=1,441)
88
Metformin (n=1,454)
1
0
Treatment difference (95% CI)
Rosiglitazone vs metformin 6.9 (6.3 tp 7.4);
P<0.001
Rosiglitazone vs glibenclamide, 2.5 (2.0 to 3.1);
P<0.001
Rosiglitazone (n=1,456)
100
Metformin (n=342)
0
3
6
9
12
Years from randomization
Conventional treatment (n=411);
diet initially then sulphonylureas,
insulin, and/or metformin if FPG
> 15 mmol/L
UKPDS 34. Lancet. 1998:352:854-865. n=at baseline; Kahn et al (ADOPT).
N Engl J Med. 2006;355(23):2427-2443.
0
0
1
2
3
4
Years
Annualized slope (95% CI)
Rosiglitazone, 0.7 (0.6 to 0.8)
Metformin, -0.3 (-0.4 to -0.2)
Glibenclamide, -0.2 (-0.3 to 0.0)
5
Hypoglycaemia
The major limiting factor to achieving intensive glycaemic
control for people with type 2 Diabetes
Briscoe VJ et al. Clin Diab. 2006;24:115-121.
Clinical consequences of hypoglycaemia
• Hospital admissions:
– Prospective study1 of well-controlled elderly T2D patients—25% of
hospital admissions for diabetes for severe hypoglycaemia
• Increased mortality:
– 9% in a study2 of severe SU-associated hypoglycaemia
• Road accidents caused by hypoglycaemia events3:
– 45 serious events per month
1. Diab Nutr Metab. 2004;17:23-26. 2. Horm Metab Res Suppl. 1985;15:105-111. 3. BMJ. 2006;332:812.
Multicentre study funded by Dept for
Transport
Determine the frequency of
hypoglycaemia in type 2 Diabetes
treated with SUs and insulin for
differing duration
Compare frequencies with
type 1 Diabetes
Prospective study over 9-12 months
of patients with good glycaemic
control
Documented severe and mild
hypoglycaemia prospectively,
supplemented with CGM x 2
UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-1147.
Hypoglycaemia in type 2 diabetes:
sulphonylureas vs insulin
• In patients treated for < 2 years, no difference in the
proportion of patients experiencing:
– severe hypoglycaemia (7% vs 7%)
– mild symptomatic (39% vs 51%)
– interstitial glucose < 2.2 mmol/L (22% vs 20%)
UK Hypoglycaemia Study Group. Diabetologia. 2007;50:1140-1147.
Hypoglycaemia in type 2 diabetes
• Hypoglycaemia symptoms common in type 2 diabetes,
occurring in up to 38% of patients1
• Hypoglycaemia is associated with :
–
–
–
–
Reduced “quality of life”
Reduced treatment satisfaction
Reduced therapy adherence
More common at HbA1c <7%
1. Diab Obes and Metab. 2008;Suppl 1:25-32.
Type 2 diabetes: greatest risk of hypoglycaemia
•
•
•
•
•
•
•
•
•
•
Use of insulin and sulphonylureas1
Older people2,3
Long-duration diabetes2
Irregular eating habits4
Exercise4
Periods of fasting4 (eg, Ramadan)
Have lower HbA1c5
Prior hypoglycaemia6-8
Hypoglycaemia unawareness9
Excessive alcohol use10
1. Asian-Pacific Type 2 Diabetes Policy Group. 4th Edition. 2005:1-58. 2. Henderson JN et al. Diabet Med. 2003;20:1016-1021. 3. Matyka K et al. Diabetes
Care. 1997;20(2):135-141. 4. Miller CD et al. Arch Intern Med. 2001;161:1653-1659. 5. Wright et al. J Diabet Complicat. 2006;20:395-401. 6. Chico A et al.
Diabetes Care. 2003;26(4):1153-1157. 7. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabet. 2008;32(suppl
1):S62-S64. 8. California Healthcare Foundation. J Am Ger Soc. 2003;51(Suppl 5):S265-S280. 9. Amiel SA et al. Diabet Med. 2008;25(3):245-254.
10. Salti L. Diabetes Care. 2004.
Hypoglycaemic clamp study of healthy men
– symptom recognition is lower in older men
Plasma Glucose, mg/dL
Young Men Without Diabetes
14
Elderly Men Without Diabetes
12
90
10
8
72
6
4
54
2
36
–40
0
40
Glucose infusion
maintained at
5 mmol/L
80
Glucose infusion
reduced stepwise
from 5 to 2.4 mmol/L
Time, min
Matyka K et al. Diabetes Care. 1997;20(2):135-14.
120
160
Glucose
infusion
restored to
5 mmol/L
0
200
Change in Total Symptom Score
108
Rates of hypoglycaemia increase as HbA1c levels
decrease in patients with type 2 diabetes on OADs
40
Annual rate, %
30
20
10
0
0
4
5
6
7
8
Most recent HbA1c, %
Wright et al. J Diabet Complicat. 2006;20:395-401.
9
10
11
Awareness of hypoglycaemia
• Recognition of warning symptoms fundamental for
self-treatment and preventing progression to severe
hypoglycaemia1
• Even mild hypoglycaemia induces defects in
counter-regulatory responses and impaired awareness2
• Impaired awareness predisposes to 6-fold increase in the
frequency of severe hypoglycaemia3
• Only 15% of type 2 diabetes patients who experienced a
hypoglycaemic event reported the incident to their doctor1,4
1. McAulay V et al. Diabet Med. 2001;18:690-705. 2. Amiel SA et al. Diabetic Med. 2008;25:245-254.
3. Gold AE et al. Diabetes Carem. 1994;17:697-703. 4. Leiter LA et al. Can J Diabetes. 2005;29(3):186-192.
Normal physiological response to hypoglycaemia
4
Adrenaline release
Sweating, tremor
3
Start of brain dysfunction
Confusion/loss of
concentration
2
1
Blood glucose (mmol/L)
Coma/seizure
Brain damage
Impaired physiological response and unawareness
4
Adrenaline release
3
Sweating, tremor
Start of brain dysfunction
Confusion/loss of
concentration
2
1
Coma/seizure
Brain damage
Blood glucose (mmol/L)
Potential mechanisms of
hypoglycaemia-induced mortality
• Cardiac arrhythmias due to abnormal cardiac repolarization in
high-risk patients (IHD, cardiac autonomic neuropathy)
• Increased thrombotic tendency/decreased thrombolysis
• Cardiovascular changes induced by catecholamines
– Increased heart rate
– Silent myocardial ischaemia
– Angina and myocardial infarction
Effect of experimental hypoglycaemia on QT interval
A
QTc = 456 ms
HR = 66 bpm
5.0 mM
B
QTc = 610 ms
HR = 61 bpm
2.5 mM
What can we do?
• Progressive disease: need for therapies that influence natural
history of the disease
• Polypharmacy: education, multi-disciplinary
support, FDCs
• Simplify guidelines
• Better tolerated drugs: low risk of hypoglycaemia/
weight neutral or weight loss
The ‘ideal’ drug for type 2 diabetes
•
•
•
•
•
•
Safe
Efficacious
Durable control
Well tolerated
Low risk of hypoglycaemia
Weight neutral or weight loss
Incretin based therapies come close to this but
long-term safety and outcome data are awaited
Fixed-dose combination therapy meta-analysis of
cardiovascular drugs and adherence
Overall
Risk ratio
(95% Cl)
Study
% Weight
Dezii CM et al, 2000
0.74 (0.65, 0.84)
17.5
Dezii CM et al, 2000
0.71 (0.62, 0.80)
17.6
Eron JJ et al, 2000
0.78 (0.55, 1.11)
4.3
Geiter LJ et al, 1987
0.88 (0.55, 1.42)
2.5
Melikian C et al, 2002
0.50 (0.35, 0.71)
4.2
Melikian C et al, 2002
0.47 (0.22, 1.01)
1.0
NDC Dataset, 2003
0.81 (0.77, 0.86)
29.0
Taylor AA et al, 2003
0.89 (0.51, 1.57)
1.8
Taylor AA et al, 2003
0.74 (0.67, 0.81)
22.1
0.74 (0.69, 0.80)
100.0
Overall
.1
Heterogeneity chi2=14.49
(P=0.07)
Amer J Med. 2007;120:713-719.
1
10
Risk ratio
Favours Fixed Dose
Favours Free Drug Publication Bias (Egger’s)
Combinations
Combinations
P=0.43
Compliance decreases when switching to
non-FDC therapy
100
82
Compliance rate (%)
80
(n = 33,567)
60
77
(n = 105)
54
(n = 1,815)
40
20
0
Monotherapy
(n=33,567)
Compliance = days supplied/total days.
Modified from Melikian C et al. Clin Ther. 2002;24:460-467.
Switched to
FDC
(Glyburide/
Metformin)
Switched to
Non-FDC
(Glyburide
+ Metformin)
Fixed-dose combination therapy and diabetes:
compliance with >6,000 US patients over 6 months
90
Adherence rate (%)
80
77 *
70
60
50
40
54
30
20
10
0
Metformin and Glyburide
Glyburide/Metformin
Comparison of adjusted adherence rates in patients receiving metformin and
glyburide combination therapy and those receiving fixed-dose glyburide/metformin
combination therapy. *P = 0.001.
Clin Ther. 2002;24:3.
FDA on fixed-dose combination therapy (2005) –
advantages
• Advantages of fixed-dose combination drug therapy:
–
–
–
–
Better adherence to a therapeutic regimen
Patient convenience
Economy (cost savings)
Generation of information regarding drug compatability
and drug interactions
Federal Register. 1971;36(33):3126-3127. Am J Cardiol. 2005;96:28K-33K.
Fixed-dose combination therapy – conclusions
• In many conditions, including diabetes, combination therapy
is inevitable
• Poor adherence is common and significantly affects outcome
• FDC reduce non-adherence by ~25%
• FDC may improve long-term outcomes and makes life easier
for the adherent
Improving adherence
• We have or will have:
– Better tolerated drugs with low risk of hypoglycaemia and weight
gain, even weight loss!
– Fixed-dose combinations for some
– Possibility of once-weekly injectables coming through
The missing link:
good rapport between patient, family, and healthcare
professionals, including multi-professional support
Helping patients to accept their condition and
adhere to a management plan
Diagnosis of Type 2 Diabetes = loss of patient’s accustomed state of health
Patient’s willpower and ability to improve outcomes depend on degree
of acceptance of the serious nature of their condition
Relationship between patient and healthcare
professionals critical in this process
Lacroix A et al. Schweiz Rundsch Med Prax. 1993;82:1370-1372.
The need for good patient-healthcare professional
rapport is essential to driving treatment adherence
“My healthcare professional has
helped me understand my blood
glucose results and the
importance of regular testing.
I feel more in control of my
diabetes.”
“I don’t really monitor my blood
glucose levels. It doesn’t seem
that important.
The physician never asks me my
numbers or measurements, so
why am I doing it?”
Motivating patients to achieve and maintain glycaemic
control will drive treatment adherence
“I’ve reached my glucose
target by eating properly,
exercising more, and
taking my medicine.”
“This is great news.
Continue with the good
work and keep your blood sugar
under control – you’ll feel better for it!”
Heisler M et al. Diabetes Care. 2005;28:816-822.
Establish a partnership between the patient and the
healthcare professional
Establish rapport
Agree on
mutual agenda
Exchange
information
Work together to:
Discuss importance of
implementing change
Build confidence that
change is possible
Challenges in improving patient understanding
35% recalled receiving advice
about their medication
Patient knowledge
of oral anti-diabetes
agents
15% knew the mechanism of action
of their therapy
10% taking sulphonylureas knew
that they could cause hypoglycaemia
20% taking metformin knew it
could cause GI side effects
Expectations regarding side effects should be appropriately managed
Browne DL et al. Diabet Med. 2000;17:528-531.
Treatment adherence can only be achieved by ensuring
appropriate treatment goals
Unrealistic weight loss goals in obese patients seeking treatment
Outcome
Initial
consultation
Weight (lbs)
% Reduction
218
0
Dream
135
38
Happy
150
31
Acceptable
163
25
Disappointed
180
17
N = 60 Obese Women
Foster et al. J Consult Clin Psychol. 1997;65:79.
A multi-disciplinary team has a significant impact on
glycaemic control and hospital admissions
Hospitalizations
Hospitalizations/1,000 person-months
Change in HbA1c from baseline (%)
HbA1c
0
-0.2
-0.4
-0.6
-0.8
-1.0
-1.2
-1.4
Control
Multi-disciplinary
team
Sadur CN et al. Diabetes Care. 1999;22:2011-2017.
30
25
20
15
10
5
0
Control
Multi-disciplinary
team
Impact of implementing an educational program via a
multi-disciplinary team
Variable
Period of time after attending education courses
0 months
12 months
FPG (mmol/L)
10.2
8.7*
HbA1c (%)
8.9
7.8*
Body weight (kg)
83.0
81.0*
Systolic BP (mmHg)
154.0
143.0*
Diastolic BP (mmHg)
95.0
87.0*
Cholesterol (mmol/L)
6.2
5.4*
Triglycerides (mmol/L)
2.8
2.1*
*Significant improvement versus 0 months.
Gagliardino JJ et al. Diabetes Care. 2001;24:1001-1007.
Clear benefits of a multi-disciplinary team approach
in type 2 diabetes care
Improved
glycaemic control1,2
Improved quality
of life1
Improved treatment
adherence1,2
Decreased
CV risk2
Improved
patient follow-up1
Higher patient
satisfaction1
Lower risk of
complications2
Decreased healthcare
costs2
1. Codispoti C et al. J Okla State Med Assoc. 2004;97:201-204. 2. Gagliardino JJ et al. Diabetes Care. 2001;24:1001-1007.
Personalized care is paramount
• When dealing with a complex chronic disease
such as type 2 diabetes:
“. . . the guidance does not override the individual responsibility of
healthcare professionals to make decisions appropriate to the
circumstances of the individual patient, in consultation with the patient
and/or guardian or carer, and informed by the summary of product
characteristics of any drug they are considering.”
NICE Clinical Guidelines for the Management of Type 2 Diabetes. May 2009.
Need for personalized care: the benefits versus risks of
diabetes therapy must be assessed for each patient
Personalised care in type 2 diabetes
• The healthcare professional must agree with the individual
patient on their glycaemic target, how this can be achieved,
and measures of success
Guidelines are guidelines, not absolutes
Summary and conclusions
• Patient adherence to agreed management plans is the major
challenge in type 2 diabetes
• Poor adherence is due to many factors, including:
– tolerability issues, complexity of the disease and its co-morbidities,
lack of knowledge and support
• Therapeutic advances can help with the problem of adherence:
– modern drugs may be better tolerated with lower risk of hypoglycaemia
and weight gain
– increasing availability of fixed-dose combination therapies
• Multi-disciplinary care and a good relationship between the
patient and healthcare professionals can improve long-term
outcomes
Personalized care should be the
cornerstone of good diabetes management
Patient adherence in type 2 diabetes:
What’s the issue and how to address
Anthony Barnett
University of Birmingham and Heart of England
NHS Foundation Trust, UK