Plan for talkPlan for talk• your experience with diabetesyour experience with diabetes

• a randomized trial (DREAM) of a randomized trial (DREAM) of rosiglitazone to prevent diabetes rosiglitazone to prevent diabetes

• patient-important and surrogate patient-important and surrogate outcomesoutcomes

Your experienceYour experience• Please raise your hand if, in your Please raise your hand if, in your

clinical practice, you take care of clinical practice, you take care of patients with diabetes?patients with diabetes?

• Please raise your hand if, in your Please raise your hand if, in your clinical practice, you take care of clinical practice, you take care of patients at high risk of developing patients at high risk of developing diabetes?diabetes?

• Is there anything you do to help Is there anything you do to help prevent diabetes in such patients?prevent diabetes in such patients?

DREAM

Structured clinical Structured clinical questionquestion

• patientspatients adults with pre-diabetesadults with pre-diabetes

• interventionintervention rosiglitazone and lifestyle advicerosiglitazone and lifestyle advice

• comparatorcomparator lifestyle advicelifestyle advice

• outcomeoutcome

oral GTTfasting glucose > 6.1, < 7.0 mmol/l2 hr > 7.8, < 11.1

> 80% meds takenover 17 days

all participants receivedhealthy diet and lifestyle advice

Validity (risk of bias)Validity (risk of bias)• randomization concealedrandomization concealed

• blindingblinding– patientspatients– caregiverscaregivers– data collectorsdata collectors– adjudicatorsadjudicators

• loss to follow-up < 2%loss to follow-up < 2%

• patients analyzed as randomizedpatients analyzed as randomized

Validity – risk of biasValidity – risk of bias

hopeless perfect

0 100

What is the authors’ message?

• rosiglitazone to prevent diabetes:

• strong indication (for all)

• weak indication (for some)

• not indicated

Doctor, what do I gain by Doctor, what do I gain by taking rosiglitazone?taking rosiglitazone?

• Doc: less chance of diabetesDoc: less chance of diabetes

• Pt: what happens if I get diabetesPt: what happens if I get diabetes

• Doc: you have to take a drugDoc: you have to take a drug

• Pt: the same drug I’m taking to prevent diabetes?Pt: the same drug I’m taking to prevent diabetes?

• Doc: I could give you a drug with less problemsDoc: I could give you a drug with less problems

• Pt: I’ll take a drug every day for 3 years to lower my Pt: I’ll take a drug every day for 3 years to lower my risk of taking the same or a less toxic drug from 25 to risk of taking the same or a less toxic drug from 25 to 10%???10%???

Modelling exerciseModelling exercise

• 10,000 patients with pre-diabetes10,000 patients with pre-diabetes

• what would happen if:what would happen if:– lifestyle advice only, drugs when they lifestyle advice only, drugs when they

develop diabetesdevelop diabetes– rosiglitazone for 3 years, stop, rosiglitazone for 3 years, stop,

resume drug if develop diabetesresume drug if develop diabetes

drug no drug difference

diabetes medication 3 years 30000 3650 26350

new diagnosis of diabetes 1060 2500 HR 0.38 (CI, 0.33-0.44)

Anxiety about diabetes ?? ?? ??Costs inconvenience self-monitoring ?? ?? ??Costs and inconvenience HbA1c, lipoprotein testing, retinal exam, etc.

?? ?? ??

MI, stroke, CV death at 3 years 120 90 HR 1.39 (CI 0.81-2.37)

Heart failure, at 3 years 50 10 HR 7.03 (CI 1.6-30.9)kidney, eyes, neuropathy ?? ?? ??Peripheral edema, at 3 years 680 490 RR 1.4 (CI 1.1-1.8)Weight gain (kg), at 3 years + 1.1 -1.1 + 2.2Rare (fractures, macular edema) ?? ?? ??

What is your view?• rosiglitazone to prevent diabetes:

• strong indication (for all)

• weak indication (for some)

• not indicated

• what has gone wrong here?

What is the problem?• development of diabetes is a surrogate

• surrogate for:– mortality– cardiovascualar events (stroke, MI)– renal failure– visual impairment and blindness– anxiety– inconvenience

Patient-important and Patient-important and surrogtessurrogtes

• patient important outcomespatient important outcomes– change might mandate treatmentchange might mandate treatment

• surrogate outcomessurrogate outcomes– associated with patient-importantassociated with patient-important– change in surrogate leads to change in pt-importantchange in surrogate leads to change in pt-important

• often biologically compellingoften biologically compelling– observational studies show association suggesting causal observational studies show association suggesting causal

relationship between surrogate and pt-important relationship between surrogate and pt-important

• often practically compellingoften practically compelling– markedly markedly ↓ ↓ duration, sample size, cost of RCTsduration, sample size, cost of RCTs

Condition Surrogate Patient-important InterventionCoronary disease

Nasty looking arrhythmia

Sudden death Encainide/flecainide

Heart failure Hemodynamic function

Mortality Flosequinan, milrinone, ibopamine,

vesnarinone, xamoterol,

epoprostanolOsteoporosis Bone density Fracture Sodium fluorideCoronary risk Cholesterol Mortality ClofibrateCoronary risk LDL, HDL Coronary events Hormone

replacement therapy

Surrogate or patient-Surrogate or patient-important?important?

• blood pressure blood pressure – (stroke, MI, death)(stroke, MI, death)

• heart failure exacerbationheart failure exacerbation• cardiac output cardiac output

– (qol, exacerbations, death)(qol, exacerbations, death)• hip fracturehip fracture• vertebral fracture vertebral fracture

– (pain, deformity)(pain, deformity)• development/increase in albuminuria development/increase in albuminuria

– (dialysis)(dialysis)• asymptomatic DVT asymptomatic DVT

– (symptomatic DVT, PE) (symptomatic DVT, PE) • development of diabetes development of diabetes

Conclusion• beware surrogate outcomes

• if intervention harmless, no cost, can rely on surrogate

• if intervention has harms or costs, demand evidence of effect on patient-important outcomes