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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