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Effective and Cost-Effective
  Treatment for Diabetes




           Edwin Gale



          Edwin Gale
      University of Bristol, UK
I have no financial conflicts of
            interest
Effective and Cost-Effective Treatment


      The scope of the problem

      What are we trying to achieve?

      Choosing the right treatment
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!
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
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
Estimated Numbers with Diabetes
   (in millions) in 2000 and 2030




Western Countries   Growing economies
Edwin gale.cost effective diabetes treatment
Diabetes Prevalence as % Population in Denmark




                               Courtesy of Bendix Carstensen
Diabetes Prevalence as % Population in Denmark




                               Courtesy of Bendix Carstensen
The Affluent Phenotype


   BP               Lipids



Atheroma            Glucose

           Cancer
Excess calorie intake is a major driver of
        the affluent phenotype …


 … and reduced calorie intake reverses
         most Edwin Gale
              of its features
Incidence of diabetes in Oslo, 1925-54




                              Westlund 1966
Diabetes Mortality in the UK, 1938-58
          World War II




Deaths/
100k




                               Trowell, 1962
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
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
Effective and Cost-Effective Treatment


      The scope of the problem

      What are we trying to achieve?

      Choosing the right treatment
What are we trying to achieve?



  1. Near-normal glucose control?

  2. Near-normal life expectancy?

  3. Near-normal life quality?
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
Lifetime Risk of Blindness by Age at
                Diagnosis and HbA1c
n/1000




                    Age at diagnosis
                                    Ann Int Med 1997;127:788
Lifetime Risk of ESRF by Age at Diagnosis
                    and HbA1c
n/1000




                 Age at diagnosis
                                 Ann Int Med 1997;127:788
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
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
HRs for CV outcomes, DM vs non-diabetes




Emerging Risk Factors Collaboration (EFRC), Lancet 2010;375:2215-22
Emerging Risk Factors Collaboration (EFRC), NEJM 2011;364:829-41
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
Numbers Needed to Treat
       [To prevent 1 CVD event]



Glucose (HbA1c 0.9%) :                   119

Cholesterol trials (1mM)                 44

Blood Pressure trials (10/6mmHg)         34


                           Yudkin et al, Diabetologia 2010
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
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
Relationship Between Glycated Haemoglobin and
          Mortality in 47,970 Patients
   Oral therapy            Insulin




                     UK General Practice Research Database,
                     Currie et al, Lancet 2010
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
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
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
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)
Effective and Cost-Effective Treatment


      The scope of the problem

      What are we trying to achieve?

      Choosing the right treatment
When?

Why?   Who?    How?
When?

  Why?

Life Quality

  CV Risk

Other risks

Longevity
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
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
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
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
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
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
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)
When?

Why?           How?
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
When?

  Why?           Who?

Life Quality   Life Quality

  CV Risk        CV Risk

Other risks    Other risks

Longevity      Longevity
When?

  Why?           Who?

Life Quality   Life Quality     Prognosis,
                              patient choice
  CV Risk        CV Risk

Other risks    Other risks

Longevity      Longevity
When?

  Why?           Who?

Life Quality   Life Quality      Prognosis,
                               patient choice
  CV Risk        CV Risk

Other risks    Other risks       Established
                              vascular disease?
Longevity      Longevity
When?

Why?   Who?    How?
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
When?

    Why?             Who?         How?

                                Life Quality
Diabetes therapies previously
considered solely in terms of     CV Risk
HbA1c reduction ...
                                Other risks

                                Longevity
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?
HbA1c: Baseline vs. change




             Diabetes Care 2006;29:2137
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
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
Glucose-lowering Agents
Core therapies:
                   Biguanides
                   Sulfonylureas
                   Human Insulin
Newer therapies:
                   Thiazolidinediones
                   DPP-4 inhibitors
                   GLP-1 agonists
Other:
                   Acarbose
                   Meglitinides
                   SGLT-2 inhibitors
ADA / EASD Guidelines
                                  Revised Treatment Algorithm
                                            At diagnosis:
STEP 1                                  Lifestyle + metformin


                     Tier 1*                                     Tier 2†
                                         HbA1C >7.0%
STEP 2

         Add basal           Add                                Add GLP-1   Add pioglitazone
          insulin        sulfonylurea                            agonist         ± SU




STEP 3                                   Intensive insulin




                                            Nathan et al. Diabetes Care 2008
Core Therapies


            Lifestyle


Metformin               Human
                        insulin
              SUs
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
Reduces CV disease!



       ?              METFOR
                       MIN




  Fights cancer!
Myocardial Infarction Hazard Ratio
     (fatal or non-fatal myocardial infarction or sudden death)

Intensive (metformin) vs. Conventional glucose control




                                                                  HR (95%CI)




                                                                   UKPDS 80
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
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
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
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
Sulfonylureas




Gloyn et al, New Engl J Med 2004;350:1838-1849
Closure of the K+ channel leads
  to membrane depolarization
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
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
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
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
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
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!
Edwin gale.cost effective diabetes treatment
A Situation of Diminishing Returns
                          Analogs       DPP4s

                   SUs

                                 TZDs
                     Metformin


  Insulin




            1920         1960            2010
And Escalating Costs


                                             1500
                 Rosiglitazone

             Pioglitazone
             Sitagliptin
                                             1000    Euros/yr
                                  Analog +
                                   Lantus
Metformin                                    500
Gliclazide
                              Human

                           Pork

                                                    UK Formulary, 2006
Costs as % total
                    Costs of glucose-
                   lowering medication
                       in England




                   Currie et al, Diabet Med 2010;27:744-52
Costs as % total    Total Costs (£m)
                         Adjusted to 2008




                   Currie et al, Diabet Med 2010;27:744-52
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
Prescriptions by Cost and Volume
              (2008)




                 Currie et al, Diabet Med 2010;27:744-52
Insulin costs (£) per 1000 units




                        BNF (accessed Oct 2011)
Insulin costs (£) per 1000 units




 Cumulative excess cost of analogues to
       the NHS is ~£650 million




                             Currie et al, BMJ in press
Edwin gale.cost effective diabetes treatment
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
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
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)
Thank you
for listening

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Edwin gale.cost effective diabetes treatment

  • 1. Effective and Cost-Effective Treatment for Diabetes Edwin Gale Edwin Gale University of Bristol, UK
  • 2. I have no financial conflicts of interest
  • 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
  • 9. Diabetes Prevalence as % Population in Denmark Courtesy of Bendix Carstensen
  • 10. Diabetes Prevalence as % Population in Denmark Courtesy of Bendix Carstensen
  • 11. The Affluent Phenotype BP Lipids Atheroma Glucose Cancer
  • 12. Excess calorie intake is a major driver of the affluent phenotype … … and reduced calorie intake reverses most Edwin Gale of its features
  • 13. Incidence of diabetes in Oslo, 1925-54 Westlund 1966
  • 14. Diabetes Mortality in the UK, 1938-58 World War II Deaths/ 100k Trowell, 1962
  • 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
  • 25. Emerging Risk Factors Collaboration (EFRC), NEJM 2011;364:829-41
  • 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
  • 27. Numbers Needed to Treat [To prevent 1 CVD event] Glucose (HbA1c 0.9%) : 119 Cholesterol trials (1mM) 44 Blood Pressure trials (10/6mmHg) 34 Yudkin et al, Diabetologia 2010
  • 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
  • 36. When? Why? Who? How?
  • 37. When? Why? Life Quality CV Risk Other risks Longevity
  • 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)
  • 45. When? Why? How?
  • 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
  • 50. When? Why? Who? How?
  • 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?
  • 54. HbA1c: Baseline vs. change Diabetes Care 2006;29:2137
  • 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
  • 57. Glucose-lowering Agents Core therapies: Biguanides Sulfonylureas Human Insulin Newer therapies: Thiazolidinediones DPP-4 inhibitors GLP-1 agonists Other: Acarbose Meglitinides SGLT-2 inhibitors
  • 58. ADA / EASD Guidelines Revised Treatment Algorithm At diagnosis: STEP 1 Lifestyle + metformin Tier 1* Tier 2† HbA1C >7.0% STEP 2 Add basal Add Add GLP-1 Add pioglitazone insulin sulfonylurea agonist ± SU STEP 3 Intensive insulin Nathan et al. Diabetes Care 2008
  • 59. Core Therapies Lifestyle Metformin Human insulin SUs
  • 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
  • 61. Reduces CV disease! ? METFOR MIN Fights cancer!
  • 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
  • 67. Sulfonylureas Gloyn et al, New Engl J Med 2004;350:1838-1849
  • 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
  • 81. Prescriptions by Cost and Volume (2008) Currie et al, Diabet Med 2010;27:744-52
  • 82. Insulin costs (£) per 1000 units BNF (accessed Oct 2011)
  • 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)