ACCORD, ADVANCE & VADT. Now what do I do in my practice?

ACCORD, ADVANCE & VADT Now what do I do in my practice? Richard M. Bergenstal, MD International Diabetes Center Park Nicollet Health Services University of Minnesota Minneapolis, MN richard.bergenstal@parknicollet.com

Presenter Disclosure Information Richard M. Bergenstal, MD I have participated in clinical research, served on a scientific advisory board and/or consulted with: Eli Lilly Novo Nordisk Sanofi-Aventis MannKind I have inherited Merck stock Roche LifeScan / J&J Abbott Bayer Medtronic Intuity Valeritas Amylin Merck Pfizer ResMed Novartis I have received no personal compensation for any of these activities and all contracts are with the non-profit Park Nicollet Institute for Research & Education Current officer of the American Diabetes Association

In the News: February 7, 2008 The ACCORD Trial and Diabetes Care Diabetes Study Halted After Deaths Deaths Prompt Halt in Diabetes Study: Study of Intensive Treatment of Diabetes Curtailed Because of Increased Death Rates International Diabetes Center Park Nicollet

ACCORD: 3 Medical Strategy Questions Glycemia (open-label trial) (n=10,251) Intensive treatment (A1C<6.0%) vs Standard treatment (A1C 7.0%-7.9%) BP (open-label trial) (n=4,733) Intensive treatment (SBP <120 mmhg) vs Standard treatment (SBP <140 mmhg) Lipids (double-blind trial) (n=5,518) Fibrate to increase HDL-C and lower TG + statin to lower LDL-C vs Placebo + Statin to lower LDL-C (ACCORD Study Group, Am J Cardiol 2007;99[suppl]:21i-33i)

ACCORD Double 2 x 2 Factorial Design ADVANCE VADT Intensive (SBP<120) BP Standard (SBP<140) Lipid stain + fibrate vs statin + placebo Group A Group B Intensive Glycemic Treatment (A1C<6%) 1178 1193 1383 1374 5128* Standard Glycemic Treatment (A1C 7-7.9%) 1184 1178 1370 1391 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analyses compare marginals for main effects (ACCORD Study Group, Am J Cardiol 2007;99[suppl]:21i-33i)

Comparison of Recent Glycemia Trials ACCORD, ADVANCE and VADT Characteristic ACCORD ADVANCE VADT N 10,251 11,140 1,791 Mean Age 62 66 60.4 Duration of T2DM 10 yr 8 yr 11.5 yr History of CVD 35% 32% 40% BMI 32 28 31 Baseline A1C 8.3% 7.5% 9.4% ACCORD Study Group. N Engl J Med. 2008;358:2545-59. ADVANCE Collaborative Group. N Engl J Med 358:2560-72, 2008. Duckworth W for VADT. N Engl J Med 2009;360:129-39

Comparison of Recent Glycemia Trials ACCORD, ADVANCE and VADT Characteristic ACCORD ADVANCE VADT N 10,251 11,140 1,791 Mean Age 62 66 60.4 Duration of T2DM 10 yr 8 yr 11.5 yr History of CVD 35% 32% 40% BMI 32 28 31 Baseline A1C 8.3% 7.5% 9.4% A1C Achieved 6.4% vs. 7.5% 6.5% vs. 7.3% 6.9% vs. 8.4% RRR CVD Events 0.90 (0.78 1.04) 0.94 (0.84 1.06) 0.88 (0.74 1.05) RRR Mortality 1.22 (1.01 1.46)* 0.93 (0.83 1.06) 1.07 (0.80 1.42) ACCORD Study Group. N Engl J Med. 2008;358:2545-59. ADVANCE Collaborative Group. N Engl J Med 358:2560-72, 2008. Duckworth W for VADT. N Engl J Med 2009;360:129-39

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvascular CVD Mortality UKPDS DCCT/EDIC ACCORD Pending ADVANCE VADT Initial Trial International Diabetes Center 2008 UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008 Oct 9;359(15):1577-89. DCCT Research Group. N Engl J Med 329;977-986, 1993 Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W et al N Engl J Med 2009;360:129-39 Long Term Follow-up

Intensive Glycemic Control in Diabetes: Implications of ACCORD, ADVANCE and VADT Skyler JS. Diabetes Care. 2009;32(1):187-92

Intensive Glycemic Control in Diabetes: Implications of ACCORD, ADVANCE and VADT Glycemic targets Lowering A1C to < 7% significantly lowers the risk of microvascular complications in both type 1 and type 2 diabetes Controlled trials of more intensive glycemic control have not demonstrated a reduction in CVD risk Long-term follow-up suggests that A1C < 7% soon after diagnosis is associated with a reduction in CVD risk years later Until more evidence becomes available, the general A1C target of < 7% is reasonable For selected patients lower or higher A1C targets may be appropriate Skyler JS. Diabetes Care. 2009;32(1):187-92 Also published in Circulation and American College of Cardiology

Post ADA 2008 - ACCORD, ADVANCE, VADT I told you glucose control was not important New A1C goal should be <8% - no make that <9% I am sure it was the severe hypoglycemia that killed people I am sure it was silent hypoglycemia coupled with autonomic n. I am sure it was the weight gain that killed people I am sure it was how rapidly the A1C was lowered that killed people Those with diabetes of long duration & known heart disease died Cardiologists were right its all about lipids and blood pressure Time to rewrite guidelines and treatment algorithms ---

1. Meta analysis 2. More detailed secondary analyses of ACCORD and VADT data

A Broader View of CVD and Diabetes Implications of ACCORD, ADVANCE and VADT A few observation and much reasoning lead to error. Many observations and a little reasoning to truth Alexis Carrel

Prevention of CVD Thru Glycemic Control CVD Events and Mortality Risk Mannucci E et al. Nutr Metab Cardiovasc Dis epub ahead of print 8 May 2009

Ray et al Lancet May 2009 Meta analysis of RCT s: CVD & Death in DM Non- fatal MI All CHD events

Ray et al Lancet May 2009 Stroke Meta analysis of RCT s: CVD & Death in DM All Cause Mortality

The ACCORD and ADVANCE Glycemic Control Intensive vs Standard A1C (%) A1C (%) 9.0 8.5 8.0 7.5 7.0 6.5 6.0 10.0 9.0 8.0 7.0 6.0 5.0 Standard therapy Intensive therapy 0 1 2 3 4 5 Time (yrs) Standard control Intensive control 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) ACCORD Study Group. N Engl J Med. 2008;358:2545-59. 6 A1C 7.5% 6.4% A1C 7.0% 6.4%

INT vs STD strategy Post-Rz Differences Lower A1C Achieved median 6.4% vs 7.5% Greater use of medications: More multiple oral meds More insulin More consequences of therapy: Severe hypoglycemia Weight gain More SAEs 11% vs 2% on 4-5 oral classes 77% vs 55% on insulin 10.5% vs 3.5% w/ hypoglycemia event requiring medical assistance 28% vs 14% >10 kg gain 2.2% vs 1.6% w non-hypo SAE (NEJM 358:2545, 2008)

Can we predict what baseline characteristics increase risk of death? DEMOGRAPHICS MEDICAL HISTORY MEDICATIONS LAB TESTS Age Race/ethnicity Gender Lives alone Clinical network BMI Waist circumference Education Year of randomization Prior CVD event Prior HF DM duration Hx neuropathy Peripheral Neuropathy (MNSI) Retinal laser/surgery Visual acuity Smoking Depression Blood Pressure ECG (MI, QT) SU Metformin TZD Any insulin HCTZ ACE inhibitors Beta blockers CCB Fibrates Statins Aspirin Antidepressants A1C LDL HDL TG Serum Cr GFR (MDRD) Alb/Cr urine

Risk of Death (all-cause) in INT vs. STD Subgroups w/ significant interactions Baseline Subgroup % Deaths (N) STD % Deaths (N) INT INT vs STD Hazard Ratio Interaction P-Value Hba1c < 7.5 4.40% (1022) 7.5 to 8.4 4.09% (2200) 8.5+ 3.60% (1887) Self-report Hx Neuropathy 4.83% (1036) 4.18% (2226) 6.14% (1857) 0.0444 Yes 4.11% (1410) 7.84% (1327) 0.0008 No 3.84% (3646) 4.10% (3708) Aspirin Use Yes 3.83% (2771) 5.73% (2808) 0.0309 No 4.12% (2352) 4.14% (2320) 0 1 2 3 4 INT Better STD Better

Marginal Significance BMI (interaction p = 0.07) Anti-depressants (interaction p=0.08) Expected, But No Interaction with Treatment Age Prior history of CVD Diabetes Duration

Severe Hypoglycemia

Severe Hypoglycemia Rates in INT & STD Groups 20 15 10 5 0 INT intensive STD standard Pts w hypoglycemia events (%) Participants With Hypoglycemic Events (%) 0 1 2 3 4 5 6 7 Years

Persons more or less likely to have severe hypoglycemic event (multivariate analysis) Albumin:creatinine >300: HR 1.74 (95% CI:1.37-2.21) African American: HR 1.43 (95% CI: 1.20-1.71) Women: HR 1.21 (95% CI: 1.02-1.43) Every 1 yr increase in age: HR 1.03 (95% CI: 1.02, 1.05) BMI > 30: HR 0.65 (95% CI: 0.50-0.85)

Self-reported Antecedents to Hypoglycemia Events Reason % (n=875 events) Delayed/missed meal or ate fewer carbohydrates 58% (510) None 17% (148) Took incorrect dose of glucose lowering medication 9% (82) Cognitive decline 8% (70) Intercurrent illness 5% (44) Ingested alcohol 3% (26) Recent weight loss 3% (29) Started or increase of other medication 3% (28)

Risk of Hypoglycemia by Study Group and Average Updated A1C Incidence Per 100 Person Years 6 5 4 3 2 1 0 Intensive INT Standard STD HR for hypoglycemia by each 1% higher updated average A1C: Intensive = 1.15 Standard = 1.76 Higher A1C assoc w/ higher hypoglycemic rates within both groups 6.00 7.00 8.00 9.00 Updated Average A1C (Quintiles)

The ACCORD and ADVANCE Glycemic Control Intensive vs Standard A1C (%) A1C (%) 9.0 8.5 Standard therapy 8.0 7.5 7.0 Intensive therapy 6.5 6.0 0 1 2 3 4 5 6 10.0 Time (yrs) 9.0 8.0 Standard control 7.0 6.0 Intensive control 5.0 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (months) ACCORD Study Group. N Engl J Med. 2008;358:2545-59. A1C 7.5% 6.4% A1C 7.0% 6.4%

Hypoglycemia Rate Of A1C Change From BL To 4 Months Incidence Per 100 Person Years 6 5 4 3 2 1 0 INT STD -1.00 0.00 1.00 2.00 3.00 HR for hypoglycemia by initial 4-month decrease of an additional percentage point in A1C: Intensive = 0.86 Standard = 0.72 Greater reduction in A1C assoc with lower hypoglycemia rates Baseline A1C Minus Month 4 A1C (Quintiles)

No severe hypoglycemia At least one severe hypoglycemia event HR (Hypo vs no Hypo) (95% CI) Mortality by Study Group and Hypoglycemia Occurrence STD (n=175 w/ events) 1.0% / year 180 deaths 17,516 PYs 4.9% / year 17 deaths 345 PYs 2.87 (1.73-4.76) INT (n=528 w/ events) 1.3% / year 220 deaths 17, 031 PYs 2.8% / year 34 deaths 1,208 PYs 1.28 (0.88-1.85) Mortality rate higher in those w hypoglycemia regardless of treatment group HR INT vs STD (95% CI) 1.24 (1.02-1.52) 0.55 (0.31-0.99) In those w hypoglycemia, mortality rate lower in INT than STD group PY = Person Years

Etiologic Fraction of Deaths Possibly Due to Severe Hypoglycemia Intensive Group Etiologic Fraction: 3.4% X Number of deaths: 254 = Number of deaths potentially attributable to hypoglycemia: 9 Standard Group Etiologic Fraction: 5.4% X Number of deaths: 197 = Number of deaths potentially attributable to hypoglycemia: 11

Association of Average A1C with Mortality by Tx Strategy Did the Intensive Patients who died have lower A1C s? Hazard Ratio for 1% higher average updated A1C (95% CI), w group assignment added to other covariates: INT strategy 1.66 (1.46, 1.89) p=0.0001 STD strategy 1.14 (0.95, 1.38) Interaction between INT and STD: p=0.17 p=0.0007 Relationships between average A1C and mortality differed between treatment strategies

Risk of Death over Range of Ave. A1C Smoothed spline plots with 95% confidence intervals, adjusted for all covariates Steady increase of risk from 6% to 9% A1C in INT strategy Log HR of Mortality Relative to STD @ 6% A1C INT STD 6 7 8 9 Excess risk with Average INT vs STD A1Cabove A1C 7%

Rates of Death During Treatment over a Range of 1-year Change in A1C Excess risk with INT vs STD strategy occurred when INT participants failed to reduce A1C in year 1 Death rates per year INT STD 0.0 A1C decline 0.5 from 1.0 baseline over 1.5 12 months 2.0 (%)

ACCORD Conclusions: Main Results In people with longstanding T2DM and either CVD or additional CV risk factors, over average 3.5 years A strategy using currently available therapies to target near-normal A1C levels, compared to a more conventional strategy Increased mortality Did not reduce a composite of major CVD events (primary outcome) (NEJM 358:2545, 2008)

ACCORD Conclusions: Subgroups and Hypoglycemia Excess mortality from INT vs STD consistent across numerous pre-specified and ad-hoc BL subgroups Regardless of treatment assignment: Hypoglycemia risk is higher in women, African Americans, those w/ renal complications Hypoglycemia event preceded by missed or nontypical meals Severe hypoglycemia is associated with a higher risk of mortality Although hypoglycemia was higher in INT than STD groups, there is no evidence that the hypoglycemia accounted for the higher mortality in INT

ACCORD Conclusions: Achieved A1C Higher risk of death associated with higher average updated A1C, esp. in INT Lower achieved A1C not associated with hypoglycemia events nor with mortality: Excess risk of death in INT group occurred in those whose average achieved A1C was higher than 7% More rapid reduction of A1C not assoc with higher risk of death in INT group Excess risk in INT vs STD occurred when INT participants failed to reduce A1C in year 1 Results suggest that, using an intensive strategy: Some with T2DM can safely achieve A1C levels below 7% Others who do not readily reduce A1C may be at risk if they persist with this strategy

ACCORD Double 2 x 2 Factorial Design Intensive (SBP<120) BP Standard (SBP<140) Lipid stain + fibrate vs statin + placebo Group A Group B Intensive Glycemic Treatment (A1C<6%) 1178 1193 1383 1374 5128* Standard Glycemic Treatment (A1C 7-7.9%) 1184 1178 1370 1391 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analyses compare marginals for main effects (ACCORD Study Group, Am J Cardiol 2007;99[suppl]:21i-33i)

After Statin therapy.what? 60 yr old man Post-MI x 3 yrs Hypertension- treated BMI 29 HbA1c 7.0% TC 250 LDL 165 TG 250 HDL 35 Non HDL 215 40 mg simvastatin HbA1c 7.0% TC 170 LDL 95 TG 200 HDL 35 Non HDL 135

Trial N Mean SBP < intense Mean SBP > intense CVD Risk Reduction SHEP 583 155 146 22-56% Syst-EUR 492 162 153 62-69% HOT 1,501 148 144 30-67% UKPDS 1,148 154 144 32-44% ABCD 470 138 132 No CVD ADVANCE 11,140 140 135 14% mortality Cushman, et al. Am J Cardiol 2007;99[suppl]:44i 55i; Patel, et al. Lancet. 2007;370:829 840

Achieved Systolic Pressures Means +/- 95% Confidence Intervals Mean # Meds: 1.6 1.9 2.1 2.2 2.3 Mean # Meds: 1.6 3.2 3.4 3.5 3.4 Mean SBP (mmhg) 140 135 130 125 120 115 0 1 2 3 4 5 6 7 Years Post-Randomization Intensive Standard

ACCORD SBP ADV UKPDS UK Prospective Diabetes Study

Current BP target in diabetes <130/80 mmhg If the ACCORD BP trial demonstrates a reduction in major CVD outcomes: Recommended SBP goal in DM may be <120 mm Hg If ACCORD does not show CVD benefits for the lower BP goal, guidelines may be changed to reflect the evidence from ADVANCE supporting a higher goal (like systolic135 mmhg).