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T2DM Control: Targeting Values or Targeting Patients?

Today’s speaker has no conflict of interest to disclose.

The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical

education for physicians.

UAB School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit (s) Physicians should only claim credit

commensurate with the extent of their participation in the activity.

Gustavo R. Heudebert, MDDivision of General Internal Medicine

Road Map

BackgroundDCCT and DCCT/EDICUKPDS and follow-up Interpreting RCT

Glycemic Control TrialsACCORD/ADVANCE/VADT

Targeting patients: systematic reviews and cohort study

Summary and recommendations

DCCT

Randomized controlled trialType 1 diabetics; 1880 patients Intense versus conventionalA1C of 7.2% versus 9.1%

Decrease in microvascular complicationsRetinopathy (75% RRR)Peripheral neuropathy (60% RRR)Microalbuminuria (40% RRR)

Increase in hypoglycemic episodesDCCT Research Trial Group. NEJM 1993; 329: 977-86

UKPDS Trial

Randomized controlled trialType 2 diabetics; 4000 patients Intense versus conventional control (diet)

A1C 7% versus 7.9%Sulfonylureas / insulinMetformin subgroup (> 120% IBW)

Decrease in microvascular complications (25% RRR)Photocoagulation for retinopathyUK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837-53

UKPDS

Macrovascular complicationsFor sulfonylurea/insulin versus diet

RRR of 16% (0.052)For metformin versus diet

DCCT / EDIC

Epidemiological studyFollow-up of DCCT patients

Length of follow-up: 6.5 yearsSimilar A1C control after 24 months

7.9% versus 8.2%Persistence of benefit

Retinopathy / Peripheral neuropathy / Microalbuminuria

DCCT/EDIC Research Group. NEJM 2000;342:381-9

DCCT / EDIC

Seventeen years follow-upTrial from 1986-1993“Similar A1C” four years after termination of trial

Outcomes of interestCardiovascular disease (57% RRR)Stroke, non fatal MI, and death from

cardiovascular disease (42% RRR)

DCCT / EDIC Research Study Group. N Engl J Med 2005;353:2643-53

UKPDS Follow-Up

Ten year follow-upSulfonylurea or insulinDietMetformin (> 120% body weight)

After one year post-trialSimilar levels of A1C

OutcomesMicrovascular / Macrovascular

Summary for Type 1 Diabetes

Short term improvement in microvascular outcomesRetinopathy / neuropathy / albuminuria

Long term maintenance in improved microvascular outcomes

Long term improvement in macrovascular outcomes

Summary for Type 2 Diabetics

Improvement on composite outcome Mostly a reduction on the need for photocoagulation Near statistical significant reduction of myocardial

infarction Suggestion metformin beneficial

Long term outcomes Maintenance of microvascular outcomes Suggestion in improvement of macrovascular

outcomes

RCT and Causality

Pinnacle of EvidenceBest suited to address hypothesis of difference

between interventions Intervention A “different” than Intervention B

“Statin lowers cholesterol more than niacin”

Ill suited to establish causality between intervention and outcome Intervention A explains certain outcome

“High Cholesterol is related to CAD”

RCT and Causality

RCT reports an average effectDecrease in % CAD per mg decrease of LDL-C

Some patient derive benefit but other not If no downside to intervention clinically

unimportant

Summary

Risk for outcome of interest highly variable in RCT

Summary results do not address issue of patient variability

Multilevel risk assessment not done routinelyDifficult to apply “average” results from RCT

Potential for harm based on intervention

VADT

Randomized controlled trialMulticenter trial among patients with T2DM1791 military veterans with poorly controlled

diabetes Intense versus conventional treatmentStratified by use of insulin, site, and prior

macrovascular eventGoal of 1.5% difference in A1C

Duckworth W et al. N Engl J Med 2009;360:129-139

VADT

Composite MacrovascularAMI, stroke, death from CV disease, surgery for

CAD/CVA/PVD, new or worsening CHF, amputation for gangrene

MicrovascularIntervention

Two oral agents (based on BMI); addition of insulin to aim at A1C less 6% or less than 9%

Duration of 6 yearsDuckworth W et al. N Engl J Med 2009;360:129-139

VADT

Age 60

Male 95%

Known CAD 40%

Duration of DM 11.5 years

Glycated Hgb 9.4%

Duckworth W et al. N Engl J Med 2009;360:129-139

ACCORD Trial

Multicenter trial in US and CanadaSponsored by NHLBI77 centers across 7 networks

Participants10,251 patientsA1C greater than 7.5%Age 40 to 79 years

Age 55 to 79 if no CV event but with 2 risk factors

The ACCORD Study Group. N Engl J Med 2008;358:2545-2559

ACCORD Trial

InterventionA1C less than 6% versus 7% to 7.9%More frequent follow-up in tight control groupRestricted formulary

CompositeNon fatal AMI, non fatal CVA, and death from

cardiovascular causesStudy stopped at 7th interim analyses

The ACCORD Study Group. N Engl J Med 2008;358:2545-2559

ACCORD Trial

Age 62 years

Male 62%

Prior CAD 36%

Duration of DM 10 years

Glycated Hgb 8.3%

The ACCORD Study Group. N Engl J Med 2008;358:2545-2559

Summary of RCT

No improvement in macrovascular outcomes with better A1C

Potential risk for harm (ACCORD)

Benefit for certain subgroups (?)

Summary of RCT

Older patients with T2DM

Poor glycemic control

High cardiovascular risk profile

Long duration of disease

Systematic Reviews

Two recent meta-analysis (2009)Lancet: five RCTs including the PROactive trialAnnals: five RCTs (UKPDS 33 and 34) but not

included PROactiveBoth studies included ACCORD, ADVANCE and

VADTBoth conducted rigorous literature searches

and analyses

Ray et al. Lancet 2009; 373:1765-72Kelly at al Ann Intern Med. 2009;151:394-403

Systematic Reviews

Lancet Annals

Coronary Events 0.83 0.89

All CV Events 0.85 0.90

Strokes 0.93 0.98

Mortality 1.02 0.98

Ray et al. Lancet 2009; 373:1765-72Kelly at al Ann Intern Med. 2009;151:394-403

Comorbidity and Outcomes

Observational study (1999-2004)Diabetics patients

Random sample from community based diabetes or general practices in Italy

No age, treatment. Or duration of diabetes restrictions

Main outcome: incident CV eventsAngina, AMI, CVA, TIA, CABG/PCI, lower limb

complications, and CV mortality

Greenfield et al. Ann Int Med 2009;151:854-860

Cohort Study

Participating physicians collected the dataMeasure of comorbidity

Total Illness Burden IndexEight dimensions (CAD/CHF, COPD, CHF, OA/RA, etc.Dichotomized by degree of comorbidity (12) and if CV-

related or not

Incident CV outcomesTwo levels of A1C (< 6.5 and < 7%)

Performance of TIBI

Survival at 5 yr Hazard Ratio

CV Events ( < 12) 83.7% 1.0

CV Events ( ≥ 12) 76.6% 1.52 (1.21-1.89)

Mortality ( < 12 ) 94.2% 1.0

Mortality (≥ 12 89.9% 1.39 (0.97-1.99)

Analyses by A1C level

Hgb A1C level Hazard RatioUnadjusted

Hazard RatioAdjusted

TIBI Score ( < 12) 0.58 (0.41-0.82) 0.6 (0.42-0.85)

TIBI Score ( ≥ 12) 0.93 (0.68-1.26) 0.92 (0.68-1.25)

Hgb A1C (< 7%)

TIBI Score ( < 12) 0.59 (0.44-0.81) 0.61 (0.44-0.83)

TIBI Score ( ≥ 12) 0.88 (0.66-1.17) 0.86 (0.64-1.14)

Summary

Comorbidity modulates the effect of glycemic control on outcomes

Lower comorbidity patients do benefit from tighter glycemic control

We need RCT to confirm above observationsWe need RCT to follow patients after trial

terminated in carefully defined risk groups

Final Recommendations

Tight glucose control in type 1 diabeticsBeneficial for microvascular complications

Have a legacy effectPossibly beneficial for macrovascular complications

Tight glucose control in type 2 diabeticsBeneficial for microvascular complications

Legacy effectBeneficial for macrovascular complications in

patients with few comorbidities