Aggressive Hyperglycemia Management

Significant hospital hyperglycemia requires close follow-up Previously diagnosed diabetes and elevated A1C Without previously diagnosed diabetes (with random BG >125 mg/dL) Pre-admission diabetes care plan requires revision Test (FBG, 2-hr OGTT) to differentiate between in- hospital hyperglycemia and T2DM once patient is metabolically stable Clement S et al. Diabetes Care. 2004;27: Conaway DLG et al. Am Heart J. 2006;152: Hyperglycemic patients Post-discharge

Glucose control in ACS patients with diabetes often unknown or undertreated at discharge NoYes (n = 235) (n = 162) (n = 58) (n = 39) Conaway DLG et al. Am Heart J. 2006;152: A1C Diabetes therapy adjusted Patients (%) N = 235 with diabetes + ACS (<7%)

EPIC-Norfolk: CV risk increases with A1C level A1C (%) WomenMen Events/ 100 persons Khaw K-T et al. Ann Intern Med. 2004;141: N = 10,232 P Trend < across A1C categories for all endpoints CVD eventsAll deaths <55–5.45.5–5.96–6.46.5–6.9≥7<55–5.45.5–5.96–6.46.5–6.9≥7  1% A1C associated with:  20% CVD events,  22% mortality

UKPDS 33: Glycemic control declines over time UKPDS Group. Lancet. 1998;352: Years from randomization Diet (conventional treatment)Sulfonylurea or insulin (intensive treatment) 6.2% (upper limit of normal) ADA target A1C, median (%) N = 3867 with newly diagnosed T2DM

Need for insulin increases over time Wright A et al. Diabetes Care. 2002;25: Chlorpropamide UKPDS 57: N = 826 with newly diagnosed T2DM Patients requiring additional insulin (%) Glipizide Years from randomization ~53% of patients required additional insulin therapy by year 6

UKPDS 33: Effect of intensive glucose control on T2DM complications Relative risk reduction (%) UKPDS Group. Lancet. 1998;352: Any T2DM-related endpoint MIAll deaths T2DM- related death Micro- vascular endpoints P = 0.34P = 0.029P = 0.44P = 0.052P = Stroke P = 0.52 A1C 7% vs 7.9% with intensive vs conventional treatment All P values vs conventional treatment

UKPDS 34: Glucose control and CV outcomes n = 1704 overweight with T2DM; n = 342 metformin group UKPDS Group. Lancet. 1998;352: Favors metformin or intensive Favors usual care All-cause mortality Metformin Intensive MI Metformin Intensive Stroke Metformin Intensive Aggregate endpointP* 012 *Metformin vs other intensive (sulfonylurea or insulin) Relative risk (95% CI)

Limitations of UKPDS Small difference in A1C between intensive and conventional groups: 7.0% vs 7.9% A1C exceeded current ADA <7% target Delay in adding multiple therapies Insufficient power to assess CV outcomes UKPDS Group. Lancet. 1998;352: Hypothesis-generating study

DCCT/EDIC: Intensive glucose control associated with reduced long-term CV risk DCCT/EDIC Study Research Group. N Engl J Med. 2005;353: Any initial CV event* Time (years) N = 1441 with type 1 diabetes, mean baseline age 27  42% Risk (9%–63%) P = 0.02  57% Risk (12%–79%) P = 0.02 CV death, nonfatal MI, stroke* 52 events 31 events 25 events 11 events DCCT ends A1C 7.4% vs 9.1% *Cumulative incidence ConventionalIntensive

EDIC year 11: Patient characteristics at mean age 45 Characteristic Intensive (n = 593) Conventional (n = 589) A1C (%) Current cigarette smoker (%)1411 BMI (kg/m 2 ) Duration of diabetes (yr)2423 Blood pressure (mm Hg)120/75121/75 Hypertension (%)*3841 Hyperlipidemia (%) † 5248 Albumin excretion rate (%) ≥40 mg/24 hr917 ‡ ≥300 mg/24 hr2 6 ‡ *BP ≥140/90 mm Hg; † LDL-C ≥130 mg/dL ‡ P < 0.01 vs intensive treatment DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:

Glycemic control and vascular disease in T2DM N = 4472; 6 randomized trials Stettler C et al. Am Heart J. 2006;152: Incidence rate ratio (95% CI) Any macrovascular* T2DM Cardiac † T2DM Peripheral vascular ‡ T2DM Cerebrovascular § T2DM Favors conventional glycemic control Favors intense glycemic control *1587 events; † 1197 events; ‡ 87 events; § 303 events 0.81 (0.73–0.91) 0.91 (0.80–1.03) 0.58 (0.38–0.89) 0.58 (0.46–0.74)

Diabetes management trials: Clinical trial horizon UKPDS DCCT/EDIC PROactive DREAM NAVIGATOR VADT ORIGIN ACCORD HEART 2D BARI 2D RECORD ADVANCE 2009 Look AHEAD 2012

Ongoing trials of glucose lowering and CV outcomes StudyPopulation (N) IntensiveUsual carePrimary outcome VADTT2DM (~1700)≤6.08-9Composite CV events ADVANCET2DM (11,140)≤6.5~7.5Major vascular events ACCORDT2DM (~10,000)<6.0~7.5MI, stroke, CV death ORIGIN*IFG/IGT/T2DM (~10,000) FPG <95 mg/dL (glargine) <7 (no insulin) CV morbidity and mortality A1C target (%) *FPG is glycemic target for intervention group National Institutes of Health (NIH). Buse JB, Rosenstock J. Endocrinol Metab Clin N Am. 2005;34: