Effective and Cost-Effective Treatment for Diabetes

Edwin Gale

Edwin Gale

University of Bristol, UK

I have no financial conflicts of interest

The scope of the problem What are we trying to achieve? Choosing the right treatment

Effective and Cost-Effective 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!

High employment, increasing disposable income, cheap food and energy (and

everything that goes with these things) are changing the phenotype of the

human species

A Century of Economic Growth

The changing phenotype of the human species (affluent variety) Diabetologia 2004;47:1339-1342

Increasing height: 1 cm/decade Changing body proportions Increasing weight-to-height ratio Increasing longevity: 3-4 months for

every calendar year

Health Correlates of Economic Growth: A Changing Human Phenotype

Estimated Numbers with Diabetes (in millions) in 2000 and 2030

Western Countries Growing economies

Diabetes Prevalence as % Population in Denmark

Courtesy of Bendix Carstensen

Diabetes Prevalence as % Population in Denmark

Courtesy of Bendix Carstensen

Cancer

Lipids

Glucose Atheroma

BP

The Affluent Phenotype

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

Edwin Gale … and reduced calorie intake reverses

most of its features

Incidence of diabetes in Oslo, 1925-54

Westlund 1966

Diabetes Mortality in the UK, 1938-58

Deaths/

100k

Trowell, 1962

World War II

Edwin Gale

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

calorie restriction

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

Summary: The Human Phenotype

The scope of the problem What are we trying to achieve? Choosing the right treatment

Effective and Cost-Effective Treatment

1. Near-normal glucose control? 2. Near-normal life expectancy? 3. Near-normal life quality?

What are we trying to achieve?

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 quality of life

Near-normal glucose control

Lifetime Risk of Blindness by Age at Diagnosis and HbA1c

Age at diagnosis

n/10

00

Ann Int Med 1997;127:788

Lifetime Risk of ESRF by Age at Diagnosis and HbA1c

Age at diagnosis

n/10

00

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

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

Near-normal glucose control

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

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

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

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

Near-normal glucose control

Boussageon R et al. BMJ 2011

All cause mortality

OR: 1.04 (0.91 – 1.19)

Cardiovascular death

OR: 1.11 (0.96 – 1.43)

Mortality – intensive versus standard Meta-Analysis: 13 studies, 34533 patients

Relationship Between Glycated Haemoglobin and Mortality in 47,970 Patients

UK General Practice Research Database, Currie et al, Lancet 2010

Oral therapy Insulin

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

Near-normal glucose control

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

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

Check Point

160

80 80

67 63

55 38

Trial Ends

Study Ends

Mean 7.8 yr

Mean 5.5 yr

Died 24 (9 CVD) 40 (19 CVD)

Randomized

Conventional (2 dropped out)

Intensified (1 dropped out)

STENO-2 NEJM 2008;358:580

The scope of the problem What are we trying to achieve? Choosing the right treatment

Effective and Cost-Effective Treatment

When?

How? Who? Why?

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

No

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

No

Marginal

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

No

Marginal

Minor

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

No

No

Marginal

Minor

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

When?

Why?

Life Quality

CV Risk

Other risks

Longevity

Does intensified therapy benefit?

No

No

Marginal

Minor

Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85

But early intervention is beneficial!

VADT - HR for Primary Outcome in Intensive Arm

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 3 6 9 12 15 18 21 24

Duration of Diabetes (yrs)

Ha

zard

Ra

tio

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?

Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Life Quality

CV Risk

Other risks

Longevity

When?

Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Life Quality

CV Risk

Other risks

Longevity

Prognosis, patient choice

When?

Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Life Quality

CV Risk

Other risks

Longevity

Prognosis, patient choice

Established vascular disease?

When?

How? Who? Why?

When?

How? Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Life Quality

CV Risk

Other risks

Longevity

Life Quality

CV Risk

Other risks

Longevity

When?

How? Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Diabetes therapies previously considered solely in terms of HbA1c reduction ...

• Treatment A lowers HbA1c from 10.5% to 9% • Treatment B lowers HbA1c from 7.6% to 7% • Which treatment is more potent?

Spot Quiz

HbA1c: Baseline vs. change

Diabetes Care 2006;29:2137

When?

How? Who? Why?

Life Quality

CV Risk

Other risks

Longevity

Diabetes therapies previously considered solely in terms of HbA1c reduction ... But global profile now seen as more important

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

Check Point

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

Intensive insulin

At diagnosis:

Lifestyle + metformin STEP 1

STEP 2

Tier 1* Tier 2†

STEP 3

Add basal insulin

Add sulfonylurea

Add GLP-1 agonist

Add pioglitazone ± SU

HbA1C >7.0%

Nathan et al. Diabetes Care 2008

Core Therapies

Lifestyle

Metformin

SUs

Human insulin

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

METFOR MIN

Reduces CV disease!

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)

Roussel et al, Arch Int Med 2010;170:1892-99

(adjusted)

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

Benefits overstated

Unsupported claims

“Newer” may not mean „better”

Evidence base not yet established

Long term safety unknown

Much more expensive!

Disadvantages of Newer Therapies

A Situation of Diminishing Returns

1920 2010 1960

Insulin

SUs

Metformin TZDs

DPP4s Analogs

And Escalating Costs

Euros/yr

UK Formulary, 2006

1000

500

1500

Metformin Gliclazide

Rosiglitazone

Pork

Analog + Lantus

Pioglitazone

Human

Sitagliptin

Costs as % total

Currie et al, Diabet Med 2010;27:744-52

Costs of glucose-lowering medication

in England

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

Currie et al, Diabet Med 2010;27:744-52

Costs (in England)

2000 = £289.9 million 2008 = £590.4 million

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

Currie et al, BMJ in press

Cumulative excess cost of analogues to

the NHS is ~£650 million

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