This document discusses effective and cost-effective treatment for diabetes. It summarizes the key points made in the document in 3 sentences:
Intensified glucose control alone offers limited benefits for type 2 diabetes patients, as it provides only weak protection against cardiovascular outcomes and has not been shown to improve life expectancy. Combined treatment of all cardiovascular risk factors can significantly improve outcomes. The best approach is to consider a patient's individual prognosis, risks, and preferences when determining the appropriate treatment goals and therapies.
3. Effective and Cost-Effective Treatment
The scope of the problem
What are we trying to achieve?
Choosing the right treatment
4. Most of the medical
textbooks are based upon
experience gained
in Western populations.
The culture, phenotype and
genotype of diabetes differs
between major population
groups
Egyptian people should
rewrite the textbooks for
use in Egypt!
5. A Century of Economic Growth
High employment, increasing disposable
income, cheap food and energy (and
everything that goes with these things)
are changing the phenotype of the
human species
The changing phenotype of the human species (affluent variety)
Diabetologia 2004;47:1339-1342
6. Health Correlates of Economic Growth:
A Changing Human Phenotype
Increasing height: 1 cm/decade
Changing body proportions
Increasing weight-to-height ratio
Increasing longevity: 3-4 months for
every calendar year
7. Estimated Numbers with Diabetes
(in millions) in 2000 and 2030
Western Countries Growing economies
15. Calorie restriction is the only form of therapy
that strikes at the root cause of diabetes
Pharmacotherapy largely represents the
attempt to compensate for a failure of
Edwin Gale
calorie restriction
16. Summary: The Human Phenotype
Affluent humans are developing a new and
distinctive phenotype
Diseases of relative overnutrition have
emerged as the leading causes of death
Increasing longevity is a major factor in
the diabetes epidemic
17. Effective and Cost-Effective Treatment
The scope of the problem
What are we trying to achieve?
Choosing the right treatment
18. What are we trying to achieve?
1. Near-normal glucose control?
2. Near-normal life expectancy?
3. Near-normal life quality?
19. Near-normal glucose control
Offers strong protection against
microvascular complications
- but the benefit diminishes with
increasing age
But weak protection against
cardiovascular outcomes
Has not been shown to improve life
expectancy in type 2 diabetes
Intensified glucose control can reduce
20. Lifetime Risk of Blindness by Age at
Diagnosis and HbA1c
n/1000
Age at diagnosis
Ann Int Med 1997;127:788
21. Lifetime Risk of ESRF by Age at Diagnosis
and HbA1c
n/1000
Age at diagnosis
Ann Int Med 1997;127:788
22. Microvascular Disease
Risk diminishes with age and/or limited life
expectancy.
The full benefits seen in young patients with type 1
diabetes are not achieved in older people with
type 2 diabetes
23. Near-normal glucose control
Offers strong protection against
microvascular complications
But weak protection against
cardiovascular outcomes
Has not been shown to improve life
expectancy in type 2 diabetes
Intensified glucose control can reduce
quality of life
24. HRs for CV outcomes, DM vs non-diabetes
Emerging Risk Factors Collaboration (EFRC), Lancet 2010;375:2215-22
26. A 50-year-old man with diabetes loses
6 years of life expectancy
60% of the excess mortality is due
to vascular deaths
Emerging Risk Factors Collaboration (EFRC), NEJM 2011;364:829-41
28. Near-normal glucose control
Offers strong protection against
microvascular complications
But weak protection against
cardiovascular outcomes
Has not been shown to improve life
expectancy in type 2 diabetes
Intensified glucose control can reduce
quality of life
29. Mortality – intensive versus standard
Meta-Analysis: 13 studies, 34533 patients
All cause mortality
OR: 1.04 (0.91 – 1.19)
Cardiovascular death
OR: 1.11 (0.96 – 1.43)
Boussageon R et al. BMJ 2011
30. Relationship Between Glycated Haemoglobin and
Mortality in 47,970 Patients
Oral therapy Insulin
UK General Practice Research Database,
Currie et al, Lancet 2010
31. Near-normal glucose control
Offers strong protection against
microvascular complications
But weak protection against
cardiovascular outcomes
Has not been shown to improve life
expectancy in type 2 diabetes
Intensified glucose control can reduce
quality of life
32. Patient perceptions of intensive
glucose lowering
701 pts with T2DM asked re QOL utilities;
a score of 1.0 = perfect health, 0 = death
Intensive glucose control scored 0.67, or 1/3 of a
year‟s quality of life
Huang et al, Diabetes Care (2007) 30:2478
33. Check Point
Intensified glucose lowering therapy ALONE
offers limited benefits in type 2 diabetes
BUT
Combined attention to all cardiovascular risk
factors can make a dramatic difference to
outcomes
34. STENO-2
Randomized 160 NEJM 2008;358:580
80 80
Trial Ends 67 63 Mean 7.8 yr
55 38
Study Ends Mean 5.5 yr
Died 24 (9 CVD) 40 (19 CVD)
Intensified Conventional
(1 dropped out) (2 dropped out)
35. Effective and Cost-Effective Treatment
The scope of the problem
What are we trying to achieve?
Choosing the right treatment
38. When?
Does intensified
Why?
therapy benefit?
Life Quality
CV Risk
Other risks
Longevity
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
39. When?
Does intensified
Why?
therapy benefit?
Life Quality No
CV Risk
Other risks
Longevity
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
40. When?
Does intensified
Why?
therapy benefit?
Life Quality No
CV Risk Marginal
Other risks
Longevity
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
41. When?
Does intensified
Why?
therapy benefit?
Life Quality No
CV Risk Marginal
Other risks Minor
Longevity
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
42. When?
Does intensified
Why?
therapy benefit?
Life Quality No
CV Risk Marginal
Other risks Minor
Longevity No
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
43. When?
Does intensified
Why?
therapy benefit?
Life Quality No
CV Risk Marginal But early
intervention
Other risks Minor is beneficial!
Longevity No
Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143
Yudkin et al, Diabetologia 2010;53:2079-85
44. VADT - HR for Primary Outcome in
Intensive Arm
1.4
1.2
Hazard Ratio
1
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24
Duration of Diabetes (yrs)
46. Comorbidity and Glucose Control, New
onset patients aged 60-64 yrs
Comorb. Life Exp Days added
Case 1 0 14.6 yrs +106
Case 2 3 9.7 yrs + 44
Case 3 7 4.8 yrs + 8
Huang et al, Ann Int Med (2008) 149:11-19
47. When?
Why? Who?
Life Quality Life Quality
CV Risk CV Risk
Other risks Other risks
Longevity Longevity
48. When?
Why? Who?
Life Quality Life Quality Prognosis,
patient choice
CV Risk CV Risk
Other risks Other risks
Longevity Longevity
49. When?
Why? Who?
Life Quality Life Quality Prognosis,
patient choice
CV Risk CV Risk
Other risks Other risks Established
vascular disease?
Longevity Longevity
51. When?
Why? Who? How?
Life Quality Life Quality Life Quality
CV Risk CV Risk CV Risk
Other risks Other risks Other risks
Longevity Longevity Longevity
52. When?
Why? Who? How?
Life Quality
Diabetes therapies previously
considered solely in terms of CV Risk
HbA1c reduction ...
Other risks
Longevity
53. Spot Quiz
• Treatment A lowers HbA1c from
10.5% to 9%
• Treatment B lowers HbA1c from 7.6%
to 7%
• Which treatment is more potent?
55. When?
Why? Who? How?
Diabetes therapies previously Life Quality
considered solely in terms of
CV Risk
HbA1c reduction ...
Other risks
But global profile now
seen as more important Longevity
56. Check Point
Most patients have been exposed to multiple
treatments
RCT evidence does not (with some exceptions)
allow us to assess the global impact of specific
therapies upon cardiovascular risk
60. Lifestyle …
Is the starting point for any treatment
No treatment for diabetes can work effectively
without adjustment of lifestyle
Diabetes conferences are 90% about
pharmacology and 10% about human behaviour
Real world therapy is the other way round
62. Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (metformin) vs. Conventional glucose control
HR (95%CI)
UKPDS 80
63. Metformin in Patients with
Established Atherosclerosis
Method:
Comparison of 2 year mortality in 19,691
patients with diabetes and known vascular
disease, treated with or without metformin,
in the REACH registry.
Roussel et al, Arch Int Med 2010;170:1892-99
64. Metformin in Patients with
Established Atherosclerosis
+Metformin -Metformin
% Mortality 6.3 (5.2-7.4) 9.8 (8.4-11.2%)
Hazard Ratio 0.76 (0.65-0.89)
(adjusted)
Roussel et al, Arch Int Med 2010;170:1892-99
65. Benefits of Metformin
(Hazard Ratios)
Age 65-80 0.77 (0.62-0.95)
Heart failure 0.69 (0.54-0.90)
GFR 30-60 0.64 (0.48-0.86)
MF + INS 0.64 (0.46-0.89)
Roussel et al, Arch Int Med 2010;170:1892-99
66. Metformin: Summary
Mechanism of cardiovascular protection
unclear – related to mechanism of
cancer protection?
Observational studies to date show
consistent reductions in overall and
cardiovascular mortality
68. Closure of the K+ channel leads
to membrane depolarization
69. KATP channels
Transducers between intracellular energy metabolism
and electrical excitability
Found in many tissues including heart and brain
Mostly closed in tissues outside the beta cell; open in
response to ischaemia, hormones or neurotransmitters
In cardiac muscle and neurones the reduction in
electrical activity protects against damage
Frances Ashcroft, J Clin Invest 2005;115;2047-58
70. Variant forms of the channel
Kir 6.2 SUR1 beta cells
Kir 6.2 SUR2A cardiomyocytes
Kir 6.2 SUR2B arterial smooth muscle
All sulfonylureas show
some cross-reactivity
71. Potential cardiovascular consequences
of failure to open KATP channels
The default setting for cardiovascular KATP
channels is closure. Opening results in -
• Limitation of myocardial damage during ischaemia
• Loss of preconditioning
• Masking of ST segment elevation
• Loss of smooth muscle relaxation in coronary
arteries
Bell, CMAJ 2006;174:185-6
72. Myocardial Infarction Hazard Ratio
(fatal or non-fatal myocardial infarction or sudden death)
Intensive (SU/Ins) vs. Conventional glucose control
HR (95%CI)
UKPDS 80
73. Sulfonylureas: Summary
No clear evidence that theoretical risk
translates into actual risk
No clear evidence that prognosis worse
after myocardial infarction
Best avoided in interventional cardiology
Gliclazide probably safer than glibenclamide
74. Disadvantages of Newer Therapies
Benefits overstated
Unsupported claims
“Newer” may not mean „better”
Evidence base not yet established
Long term safety unknown
Much more expensive!
76. A Situation of Diminishing Returns
Analogs DPP4s
SUs
TZDs
Metformin
Insulin
1920 1960 2010
77. And Escalating Costs
1500
Rosiglitazone
Pioglitazone
Sitagliptin
1000 Euros/yr
Analog +
Lantus
Metformin 500
Gliclazide
Human
Pork
UK Formulary, 2006
78. Costs as % total
Costs of glucose-
lowering medication
in England
Currie et al, Diabet Med 2010;27:744-52
79. Costs as % total Total Costs (£m)
Adjusted to 2008
Currie et al, Diabet Med 2010;27:744-52
80. Costs as % total Total Costs (£m)
Adjusted to 2008
Costs (in England)
2000 = £289.9 million
2008 = £590.4 million
Currie et al, Diabet Med 2010;27:744-52
83. Insulin costs (£) per 1000 units
Cumulative excess cost of analogues to
the NHS is ~£650 million
Currie et al, BMJ in press
85. Overall Summary
Metformin emerges as “best buy”
The disadvantages of the sulfonylureas
have been over-stated
Analogue insulins have marginal benefits only
in type 2 diabetes
Newer therapies should be reserved for
second line use
86. Where Next?
Future clinical trials will need to evaluate
global risks and benefits of individual
therapies (and combinations) rather than
focusing on glucose-lowering efficacy
87. The Physician’s Prayer
From inability to let well alone,
From too much zeal for the new and contempt for
what is old,
From putting knowledge before wisdom,
Science before art and cleverness before common sense,
From treating patients as cases
And from making the cure of the disease more grievous
than the endurance of the same,
Good Lord deliver us.
Sir Robert Hutchison (1871-1960)