Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease CVD Mortality and/or Events? Presenters: Jeff Probstfield, MD—University of Washington Irl B. Hirsch, MD—University of Washington Eliot A. Brinton, MD—University of Utah Paul Rosenblit, MD—University of California, Irvine Moderator:

Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease Total Mortality and/or CVD Events? Jeff Probstfield, MD Professor of Medicine in the Division of Cardiology Adjunct Professor of Epidemiology, Director of the Clinical Trials Division University of Washington Seattle, WA 2

ACCORD Trial Overall Goal To determine whether CVD event rates can be reduced in people with diabetes by intensively targeting three important CVD risk factors: hyperglycemia, dyslipidemia, and high blood pressure. Three trials in one research program Double 2 by 2 factorial design Buse, JB, et al, AmJCard 2007 99:21i-33i.

DSMB Recommendation and NHLBI Decision NHLBI/NIH decision: Discontinue intensive glycemia treatment Transition all participants to the standard glycemia treatment No interaction between BP and Lipid Trial Components and Glycemia Intervention. Continue the BP and Lipid trials “These trials continue to address important questions” (NHLBI Press Release, February 6, 2008) 4

Glycemia Trial Research Question In middle aged/older people with type 2 DM at high risk for a CVD event, does a therapeutic strategy that targets an A1C < 6.0% reduce CVD event rates more than a strategy that targets an A1C between 7.0% & 7.9% (with the expectation of achieving a median level of 7.5%)? Buse, JB, et al, AmJCard 2007 99:21i-33i.

Glycemia Trial Rationale Study Mean A1C (Intense) Mean A1C (Control) Relative Risk Reduction for CVD (95% CI) UKPDS (I/SU) 7.0% 7.9% 16% (0,29) UKPDS (Met) 7.4% 8.0% 39% (11,59) Kumamoto 7.1% 9.4% 46% (NS) VACSDM 9.3% -56% (-170,10) DIGAMI 29% (4,51) UGDP(IVAR) FPG 130-146 mg/dL 170-186 mg/dL 9% (NS) Observational studies supportive Each 1% higher A1C associated with 18% greater risk of CVD1 CVD-glucose relationship extends into the normal range Clinical trials inconclusive2 1. Selvin E, et al. Ann Intern Med. 2004;141:421-431. 2. Goff DC Jr, et al. Am J Cardiol. 2007;99[suppl]:4i-20i.

Double 2 X 2 Factorial Design BP Lipid Intensive (SBP<120) Standard (SBP<140) Statin + Masked Study Drug Statin + Masked Study Drug Intensive Glycemia (A1C<6%) 1178 1193 1383 1374 5128* Standard Glycemia (A1C 7-7.9%) 1184 1178 1370 1391 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analyses compare the marginals for main effects Buse, JB, et al, AmJCard 2007 99:21i-33i.

Participant Eligibility Stable Type 2 Diabetes for 3+ months A1C >7.5% AND <9% (more meds) OR <11% (fewer meds) Age 40-79 + previous CVD events OR Age 55-79 with: anatomical ASCVD, albuminuria, LVH OR > 2 CVD risk factors (dyslipidemia, hypertension, smoking, obesity) BMI < 45; Cr < 1.5 (133 uM) No frequent/recent serious hypoglycemia Able/willing to take insulin, do glucose monitoring Eligible for BP or Lipid Trial Buse, JB, et al, AmJCard 2007 99:21i-33i.

ACCORD Outcomes Primary: Secondary/Other: First occurrence of nonfatal MI OR Nonfatal Stroke OR CV Death Secondary/Other: Each component of 10 Expanded CVD: 10 + Revasc & HF Hosp Total mortality Microvascular (nephropathy, neuropathy, eye) Eye photo substudy (N = 3537) HRQL (N = 2053); Cost (N = 4311) MIND: cognition, brain volume (MRI) Falls/Fractures/BMD Buse, JB, et al, AmJCard 2007 99:21i-33i.

A1C Distribution Standard Rx Goal Intensive Rx Goal Dec 10

A1C Distribution: 48 Mo. Standard Rx Goal Intensive Rx Goal Dec December 2007 11

Median A1C and Interquartile Ranges ACCORD Study Group, NEJM 2008 358:2545-2549.

All Cause Mortality ACCORD Study Group, NEJM 2008 358:2545-2549. 1.41%/yr 1.14%/yr HR = 1.22 (1.01-1.46) P = 0.04 ACCORD Study Group, NEJM 2008 358:2545-2549.

Primary & Secondary Outcomes Intensive N (%) Standard HR (95% CI) P Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16 Secondary Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04 Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004 Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74 CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02 CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17 ACCORD Study Group, NEJM 2008 358:2545-2549.

Primary & Secondary Outcomes Intensive N (%) Standard HR (95% CI) P Primary 352 (6.86) 371 (7.23) 0.90 (0.78-1.04) 0.16 Secondary Mortality 257 (5.01) 203 (3.96) 1.22 (1.01-1.46) 0.04 Nonfatal MI 186 (3.63) 235 (4.59) 0.76 (0.62-0.92) 0.004 Nonfatal Stroke 67 (1.31) 61 (1.19) 1.06 (0.75-1.50) 0.74 CVD Death 135 (2.63) 94 (1.83) 1.35 (1.04-1.76) 0.02 CHF 152 (2.96) 124 (2.42) 1.18 (0.93-1.49) 0.17 ACCORD Study Group, NEJM 2008 358:2545-2549.

Primary Outcome ACCORD Study Group, NEJM 2008 358:2545-2549. 2.29%/yr HR = 0.90(0.78-1.04) P = 0.16 ACCORD Study Group, NEJM 2008 358:2545-2549.

The Question: Can the observed treatment group difference in mortality be explained by the observed post-randomization treatment group difference in severe hypoglycemia?

Severe Hypoglycemia Requiring Medical Assistance Intensive Group Annual Incidence Rate = 3.3% Standard Group Annual Incidence Rate = 1.0% ACCORD Study Group, NEJM 2008 358:2545-2549.

Background: Mortality By Severe Hypoglycemia Never Experienced a Hypoglycemic Event Experienced Hypoglycemic Event Overall Mortality Rates 1.2% / year 3.3% / year Intensive Glycemia 1.3% / year 2.8% / year Standard Glycemia 1.1% / year 4.9% / year Again, mortality is higher among participants who had experienced a Severe Hypoglycemic Event, regardless of treatment strategy ACCORD Study Group, NEJM 2008 358:2545-2549.

Experienced a Hypoglycemic Event Mortality By Treatment Group and Severe Hypoglycemia Overall Never Experienced a Hypoglycemic Event Experienced Hypoglycemic Event Intensive Glycemia 1.4% / year (257 Deaths) 1.3% / year (223 Deaths) 2.8% / year (34 Deaths) Standard Glycemia 1.1% / year (203 Deaths) (186 Deaths) 4.9% / year (17 Deaths) Hazard Ratio (95% CI) 1.22 (1.01, 1.46) 1.24 (1.02, 1.50) 0.54 (030, 0.96) Mortality Higher in Intensive Group Mortality Higher in Standard Group Interaction P < 0.01 ACCORD Study Group, NEJM 2008 358:2545-2549.

Conclusions—I Among participants who never had a severe hypoglycemic event during follow-up, mortality was greater in the intensive group. However, among participants who had a hypoglycemic event, mortality was greater in the standard group Participants who had experienced a severe hypoglycemic event were more likely to die True for both treatment groups ACCORD Study Group, NEJM 2008 358:2545-2549.

Conclusions—II We have not been able to identify a single agent, or combination, that accounts for the imbalance in mortality. Exenatide  less mortality, but used rarely and more often in Intensive Glycemia group Premixed Insulin  greater mortality, but used more often in Standard Glycemia group Bolus Insulin  greater mortality, but no difference in mortality hazard ratios by randomized group and we don’t know if the relationship with mortality is a reflection of use or the participants to whom it was given Approximately a 20% increase in mortality associated with Intensive Glycemia even after controlling for participant characteristics and post-randomization use of glycemia medications. ACCORD Study Group, NEJM 2008 358:2545-2549.

Identifying a “Cause” of the Higher Mortality ACCORD identified a previously unknown harm of a strategy of intensive glucose lowering in high-risk individuals with T2DM ACCORD was designed to test a therapeutic strategy, not a specific component of the strategy or specific drug(s); numerous factors differed between the randomized groups In a strategy trial, potential causes are difficult, if not impossible, to separate out from other post-baseline factors that differ by group Example: An ACCORD participant may or may not be on a drug for various reasons, so we can’t separate out effects of the drug from effects of patient characteristics that change over time (some of which were not measured) ACCORD Study Group, NEJM 2008 358:2545-2549.

Conclusion- what caused the difference ? P It’s The Strategy (the therapeutic approach to intensive glucose lowering) In This Population (with longstanding T2DM and CVD or CVD RFs) Intention To Treat analyses (comparing groups based on randomized assignment – the analysis that provides strong evidence of causality)

Which A1c Targets and Which Drugs for Diabetes? ADVANCE Study Review: Which A1c Targets and Which Drugs for Diabetes? Irl B. Hirsch, MD Professor of Medicine Division of Metabolism, Endocrinology and Nutrition University of Washington School of Medicine Seattle, WA

Differences Between ACCORD/ADVANCE BASELINE ACCORD ADVANCE # patients 10,251 11,140 duration DM (yrs) 10 8 Hx macrovasc. Dz (%) 35 32 Baseline A1C (%) 8.1 7.2 Intervention target A1C (%) <6 <6.5 insulin Rx (%) 77 vs. 55 41 vs. 24 TZD Rx (%) 92 vs. 58 17 vs. 11 Outcome (intensive vs. standard) Median A1C @ study end 6.4 vs. 7.5% 6.4 vs. 7.0% DEATH: any cause 5.0 vs. 4.0%* 8.9 vs. 9.6% NEJM 2008;358, 2630 *P<0.05

ADVANCE Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

ADVANCE Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

ADVANCE: Primary Outcomes ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

ADVANCE: Secondary Endpoints All-cause mortality: P = NS Total renal events 11% RR with intensive, P < 0.001 Eye events: P = NS CHF, PVD, neuropathy: P = NS ADVANCE Collaborative Group, NEJM 2008 358:2560-2572.

Candidate Mechanisms: TGC and CVD Events Hypoxia (remember the PDR story!) Hypoglycemia (arrhythmias, brain dysfunction, vasoconstriction, new data leading to DAN) Obesity (3 drugs resulting in weight gain) Glucose variability in long-standing diabetes (insulin deficiency)

Big Picture Messages T1 and T2DM: early meticulous glucose control can prevent microvascular and neuropathic complications T1DM: early meticulous glucose control appears to prevent CVD many years later T2DM: early meticulous glucose control appears to prevent both micro- and macrovascular disease in T2DM

The Benefit of Early Aggressive Glycemic Control Metabolic memory “Legacy effect”

Big Picture Message T2DM: patients with known CVD or long durations of DM may be harmed by meticulous control; although the mechanism(s) for this are not known, the leading candidate mechanism is hypoglycemia

More Big Picture Messages T1DM: impact of glycemia on microvascular disease not present after 20-25 years (probably true for T2DM too) After long duration of either T1 or T2DM (or known CVD), it appears BP, LDL-C and ASA use better predict CVD mortality than A1C Impact of hypoglycemia is not consistent between populations (under 5 year-olds, geriatrics, inpatient)

SO WHAT A1C TARGETS?

My Take, At Least While We Are Awaiting ADA/AACE Consensus Statements on T2DM Targets < 10 years T2DM AND no CVD: Target at least < 7% 1st line: metformin 2nd line: SFU, sitagliptin, exenatide, basal insulin (A1C < 9%) 3rd line: physiologic insulin therapy 10-15 years T2DM AND no CVD: No change from above but this population will be more likely to require insulin to reach A1C target

Possible Strategy > 15 years T2DM OR known CVD: 7-7.5% A1C Drugs with less risk of hypoglycemia Metformin, SFU unlikely to be effective with longer durations of DM Little data for TZDs, exenatide, sitagliptin Greatest risk of hypoglycemia with insulin, but also greatest likelihood of efficacy to consistent A1C levels Less hypoglycemia with basal insulin alone, but some prandial insulin required as duration of DM and A1C increases Don’t use basal insulin to replace prandial needs!

Conclusion The 4 recent studies do not negate the years of research from other clinical trials Different populations appear to have different A1C targets It appears the same in the inpatient population! It is difficult to recommend a generalization of one drug vs. another (depending on the situation) as there are so many variables and little clinical trial data to guide us General: hypoglycemia, weight gain, pregnancy, cost Specific: GI tolerability, edema, bone fx, increase CVD risk (?)

Conclusion Insulin is always an option, is under-utilized, and needs to be used in a physiologic manner in patients with severe insulin deficiency In patients with known vascular disease, even more modest A1C targets require the use of insulin analogues (as opposed to human insulins) due to the consistent data showing less hypoglycemia even though there are no differences in A1C.

Eliot A. Brinton, MD Diplomate, American Board of Clinical Lipidology Effects of Intensive vs. Standard Glucose Control on Cardiovascular Disease: the VA Diabetes Trial (VADT) Eliot A. Brinton, MD Diplomate, American Board of Clinical Lipidology Associate Professor, University of Utah Director, Metabolism Section of Cardiovascular Genetics Salt Lake City, UT

VADT: Design Subject Inclusion: DM-2 on insulin or unresponsive to maximal doses oral agents Central A1c > 7.5%, or local A1c > 8.3% No major CV events in last 6 months (MI, CVA, CV surgery) Creatinine < 1.6 mg/dL, ALT < 3x ULN N=1791 (20 centers) Prospective, randomized study of: Intensive vs. standard glycemic Rx, 5-7.5 years Background good diet & lifestyle + Rx BP & lipids (both arms) 1o endpoint: CVD composite Get to the POINT Tell what will tell Powered at 85% to detect... Abraira, C, et al, J Diab. Complic, 2003; 17: 314

VADT: Design (cont’d) Primary outcome Composite of: MI, CVA, CVD Death, CHF, PCI, CABG, “Inoperable” CAD, LE revascularization or amputation for ischemia Secondary outcomes Total mortality Angina TIA Claudication Critical limb ischemia Retinopathy Nephropathy Neuropathy Quality of life Cognitive function Cost-effectiveness Get to the POINT Tell what will tell Powered at 85% to detect... Abraira, C, et al, J Diab. Complic, 2003; 17: 314

VADT: Baseline Subject Characteristics (similar in both arms) Sex: 97% male Age: 60.4 + 9.5 y DM Duration: 11.5 + 7.7 y BMI: 31.3 + 4.6 kg/m2 A1c: 9.4 + 1.5% Race Non-Hispanic, White: 62% African-American: 17% Hispanic: 16% Other: 5% Smoking history Current: 17% Former: 55% Never: 28% Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

VADT: Glycemic Rx and Results A1c Goal by Study Arm Intensive: <7% Standard: 8-9% Method (same in both Rx arms): Metformin (BMI>27) or glimepiride (BMI<27) Rosiglitazone Insulin Other oral agents Toolbox: add any other drugs to get to Rx goals On-study A1c by Study Arm Intensive: 6.9% Standard: 8.4% Abraira, C, et al, J Diab. Complic, 2003; 17: 314

VADT: Primary Endpoint Treatment Standard Intensive N Incidence % P-value 899 263 29.3 892 231 25.9 0.11 Non-significant trend towards 12% decrease in CVD (composite) with intensive glycemic control Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

VADT: Antiplatelet/Anticoagulant, Statins and Cigarette Use (%) Cigarette Smoking Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

VADT: On-Study LDL-C (Median/IQR mg/dL) ~30% ↓ in LDL-C Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

VADT: On-Study HDL-C (Median/IQR mg/dL) ~18% ↑ in HDL-C Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

VADT: On-Study TG (Median/IQR mg/dL) ~21% ↓ in TG Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

Predictors of Initial 1o Outcome Event (Treatment by Duration Interaction) Variable HR Lower CI Upper CI p-value Prior CV event 3.30 2.50 3.69 <.0001 Age 1.33 1.19 1.49 HDL 0.83 0.76 0.91 HbA1c 1.09 1.02 1.16 0.01 Hypoglycemia 2.07 1.14 3.77 0.02 DM Duration-Std. Rx 1.01 0.99 0.5 DM Duration- Intens. Rx 1.03 1.05 Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

CVD Hazard Ratio Intensive/Standard Rx VADT: Intensive Glycemia Rx Beneficial if Started Early (DM Duration <15 years) No correlation in Std. Rx group CVD Hazard Ratio Intensive/Standard Rx p<0.0001 DM Duration (years) Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008 52

VADT: Severe Hypoglycemia N Incidence % p Impaired Consciousness Std. Rx 899 79 8.8 <0.01 Intens. Rx 892 178 20.0 Loss of Consciousness 39 4.3 91 10.2 Severe Hypoglycemia* 87 9.7 188 21.1 *Either impaired or total loss of consciousness. Some subjects had both. Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

Predictors of All-Cause Mortality Variable HR Lower CI Upper CI p-value Prior event 1.90 1.40 2.58 <.0001 Age 2. 41 2.00 2.91 Smoker 1.70 1.16 2.48 0.006 Baseline HbA1c 1.17 1.06 1.29 0.002 Hypoglycemia* (Std Rx) 5.9 2.1 16.1 0.001 Hypoglycemia (Intens. Rx) 1.28 0.40 4.05 0.7 *Also predicted primary endpoint (CVD composite) and CVD death. Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

Effect of Rosiglitazone on Time to CVD Death (Non-randomized Rx) Veterans Affairs Diabetes Trial Effect of Rosiglitazone on Time to CVD Death (Non-randomized Rx) Unadjusted Adjusted: baseline* Adjusted: baseline and time covariates** 8 mg Hazard Ratio: 0.5 1.0 1.5 4 mg *Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP **Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker In the VADT, it was better to be on Rosiglitazone than not. Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008 55

Veterans Affairs Diabetes Trial Effect of Rosiglitazone on Time to MI (Non-randomized Rx) Unadjusted Adjusted: baseline* Adjusted: baseline and time covariates** 8 mg Hazard Ratio: 0.5 1.0 1.5 4 mg *Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP **Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker In the VADT, it was better to be on Rosiglitazone than not. Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008 56

VADT: Conclusions Intensive Glycemic Rx reduces CVD if: Started early in the course of DM (<12y) Less aggressive goal (<7% vs. <6) TZD (rosiglitazone) included in Rx Hypoglycemia avoided (std Rx only?) Added to aggressive Rx of lipids & BP (especially if HDL-C increases) per Brinton, EA; after Duckworth, W and Abraira, C, Oral Presentations ADA Mtg 6/08.

Are ‘Blood Glucose Control’ Trials Less than 10 years Duration Long Enough to Show CVD Benefit?: Time to Benefit and “Legacy Effect” of Lower Glycemia Paul D. Rosenblit MD, PhD, FACE Private Solo Practice Endocrinology, Diabetes and Metabolism, and Clinical Professor of Medicine Univ. of California, Irvine School of Medicine

DCCT/EDIC: Lower Glycemia in DM-1 Diabetes Control & Complications Trial (Randomized Intervention) / Epidemiology of Diabetes Interventions & Complications (Observational F/U) Conventional Intensive 6 8 10 1 2 3 4 5 7 1 2 3 4 5 6 7 8 9 10 11 Normal Conventional Intensive 8.9% 7.1% mean 8.2% mean 8.0% A1c (%) Between group A1c difference 1.8% 7.8% 7.9% The Effects of Intensive Glycemic Control in the DCCT (with adapted time curve) This graph illustrates the median measurements of all quarterly glycosylated hemoglobin values in the conventional and intensive treatment groups. The values for the intensive-treatment group were significantly lower from 3-months until the end of the study (DCCT 1993). There were many corresponding clinical benefits seen as a result of this reduction in HbA1c levels: The risk reduction in the progression of retinopathy and nephropathy that was demonstrated in the intensive-treatment group persisted at least 4 years later, even if HbA1c levels increased (DCCT 2000). Intensive therapy reduced the development of clinical neuropathy at 5 years later by 64% (95% CI, 45% to 76%). This evidence that intensive therapy significantly reduces neuropathy suggests that neuropathy may be preventable (DCCT 1995; DCCT 1993). The DCCT is the first prospectively determined evidence that intensive therapy prevents the development of clinical neuropathy (DCCT 1995). DCCT. N Engl J Med 1993;329:977–986. DCCT. N Engl J Med 2000;342:381–389. DCCT. Ann Intern Med 1995;122(8):561–568. Normal  6.05 DCCT Study yr EDIC yr Adapted from DCCT Research Group. N Engl J Med 1993;329:977-986 DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-2653

Conventional treatment MACE (NF MI, CVA, or CVD death) Lower Glycemia in DM-1 Decreases CVD But Benefits are Delayed (DCCT-EDIC) Intervention ----------------Follow-up------------------ Conventional treatment MACE (NF MI, CVA, or CVD death) 57% RRR p=0.02) The DCCT previously demonstrated that glucose control is associated with reduced microvascular complications in type 1 diabetes. Subsequently, the UKPDS demonstrated that improved glucose control reduced microvascular complications in type 2 diabetes. Now, the DCCT/ EDIC investigators report that during the mean 17-year follow up of the DCCT cohort, intensive glucose control was associated with a 42 percent risk reduction of any cardiovascular event and a 57 percent risk reduction in nonfatal myocardial infarction, stroke or death from cardiovascular disease. This effect was observed 11 years after the end of the treatment phase of the DCCT. At this follow up time point, the mean HbA1c was 7.9% in the original intensive intervention group and 7.8% in the group that received conventional treatment during the DCCT. At the end of the intervention phase of the DCCT, the two groups differed in terms of HbA1c by 1.7% (intensive treatment: 7.4% vs. conventional treatment: 9.1%). The analyses presented in the current paper highlight that the majority of the effect to reduce cardiovascular events could be ascribed to the differences in glucose control during the active treatment phase of the DCCT. Thus, there appears to be a memory effect that produces long-term benefit. Whether improved glucose control reduces cardiovascular disease in individuals with type 2 diabetes is not totally clear. The UKPDS suggested that this was the case and the ACCORD study, which will report in a few years, should tell us so. In the meanwhile, more evidence has been provided that improved glucose control does more good than harm. – Steven E. Kahn, M.B., Ch.B. Ask a question The DCCT/EDIC set out to investigate the benefits of intensive insulin therapy in patients with type 1 diabetes mellitus, as compared with conventional therapy. 1441 patients were randomized to receive either conventional treatment that was aimed at preventing symptoms of hyper- and hypoglycaemia, or intensive treatment that was aimed at reducing fasting plasma glucose levels to 3.9 to 6.7 mmol per liter, postprandial glucose levels below 10 mmol/liter and glycosylated hemoglobin below than 6.05 percent. After a mean 6.5 years of follow-up, the DCCT ended. All patients were offered intensive treatment, particularly on the basis of the beneficial effects intensive treatment had on the prevention of microvascular complications. However, follow-up was continued. Now, after 17 years of follow-up, the pre-specified number of 50 patients in the conventional treatment arm has experienced a cardiovascular event. This allowed for the analysis of the effects of an early intensive insulin regime on macrovascular complications. Although glycemic control of both groups had already been essentially the same for over ten years, there was still a significant decrease of 42 percent in cardiovascular events in the intensive treatment arm (P=0,02). Furthermore, intensive treatment reduced the risk of severe clinical events, including nonfatal myocardial infarction, stroke, or death from cardiovascular disease, by 57 percent (P=0,02). These results are extra-ordinary, particularly if one considers that the evidence for a beneficial effect on macrovascular events was virtually absent until now. The large effect of early tight glucose control on long-term cardiovascular events not only underlines the need for strict glycemic control, but also the fact that benefits of such an intervention may only occur after prolonged follow up. --John JP Kastelein, MD   Assessment  Copyright (C) 2004 Bioexpertise, Inc. All rights reserved. Need Help? Terms. Privacy. Bioexpertise. Account. CME Faculty. Intensive treatment No. at Risk Years since entry Intensive 705 686 640 118 Conventional 721 694 637 96 DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53.

UKPDS: Lower Glycemia in DM-2 with Intensive Intervention Over 10 years HbA1c was 7·0% (6·2–8·2) in the intensive group compared with 7·9% (6·9–8·8) in the conventional group 9 Average between group A1c difference = 0.9% Conventional 8 Median A1c (%) Intensive (Sulfonylurea or Insulin) 7 Shown here is the effect of conventional treatment (circles) and intensive treatment (squares) on HbA1c. In the first year of treatment, the intensive-treatment group had a decrease in median HbA1c to the upper limit of the normal range.1 Within approximately 6 years, the HbA1c value in the intensive treatment group had progressively increased to the pretreatment value of 7%. Intensive therapy achieved significantly lower HbA1c values throughout the study, with a median difference of 0.9% over 10 years (median HbA1c of 7% in the intensive group vs. 7.9% in the conventional group, P<0.0001). However, intensive treatment did not maintain good glycemic control, a reflection of the progressive nature of type 2 diabetes.1 6 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:837-853.

After Mean 10-Years’ Follow-Up UKPDS: Aggregate Clinical Endpoints in Glucose Control Study with Between Group HbA1c Difference of Only 0.9% After Mean 10-Years’ Follow-Up Relative risk* (95% CI) Reduced Increased 0.5 risk 1 risk 2 RR P value Any diabetes-related endpoint 0.88 0.029 Diabetes-related deaths 0.90 0.34 All-cause mortality 0.94 0.44 Myocardial infarction 0.84 0.052 Stroke 1.11 0.52 Microvascular 0.75 0.0099 Patients receiving intensive treatment after 11 years of follow-up had a significantly reduced risk of experiencing any diabetes-related endpoint (P=0.029). Intensive treatment also conferred a significant 25% risk reduction in microvascular endpoints compared with conventional treatment (P=0.0099).1 For myocardial infarction, the 16% reduction in risk for the intensive-treatment group compared with the conventional-treatment group approached significance (P=0.052). There were no significant differences between conventional and intensive treatment in the relative risks of diabetes-related deaths, all-cause mortality, or stroke.1 Favors Favors Intensive Conventional *vs. conventional policy. Microvascular, NOT Macrovascular, events were reduced in UKPDS trial UKPDS Group. Lancet. 1998;352:837-853

UK Prospective Diabetes Study and Long-Term F/U Interventional Trial (Randomized, Blinded), 1977-1997 N=5,102, newly-diagnosed DM-2 (recruited 1977-1991) Median randomized follow-up 10 y (6-20 y) 10-y Post-Trial Monitoring, 1997-2007* Annual follow-up (UKPDS clinic-based x 5y, then questionnaire-based x 5y more) Median total follow-up 17 y (16-30 y) *no attempts to maintain previously assigned therapies. Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS Post-Trial Follow-Up A1c UKPDS results presented Mean (95%CI) UKPDS HbA1c diff. 0.9% end of trial UKPDS website-- http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/ Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS “Legacy Effect” of Earlier Glucose Control with Insulin or Sulfonylurea Interv. F/U Aggregate Endpoint -1997 -2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% P: 0.44 0.007 RRR = Relative Risk Reduction, P = Log Rank Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS: “Legacy Effect” of Earlier Glucose Control with Metformin in Overweight Patients Interv. F/U Aggregate Endpoint -1997 -2007 Any diabetes related endpoint RRR: 32% 21% P: 0.0023 0.013 Microvascular disease RRR: 29% 16% P: 0.19 0.31 Myocardial infarction RRR: 39% 33% P: 0.010 0.005 All-cause mortality RRR: 36% 27% P: 0.011 0.002 RRR = Relative Risk Reduction, P = Log Rank Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS Post-Trial Follow-up Blood Pressure UKPDS results presented Mean (95%CI) UKPDS website-- http://www.dtu.ox.ac.uk/index.php?maindoc=/ukpds/ Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS: No “Legacy Effect” of Earlier BP Control Interv. F/U Aggregate Endpoint -1997 -2007 Any diabetes related endpoint RRR: 24% 7% P: 0.0046 0.31 Microvascular disease RRR: 37% 16% P: 0.0092 0.17 Myocardial infarction RRR: 21% 10% P: 0.13 0.35 All-cause mortality RRR: 18% 11% P: 0.17 0.18 RRR = Relative Risk Reduction, P = Log Rank Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT 7.9 Proportion of patients with events UKPDS 15 yrs, mean F/U 10 yrs 0.9 7.0 Conventional (n=411) 35% Intensive (n=951) Metformin (n=342) 30% M vs. C P=0.017 M vs. I P=0.11 I vs. C P=0.029 Standard A1c Between group A1c difference Intensive A1c Trial 20% This Kaplan-Meier plot shows that patients treated with metformin had a 42% lower risk of diabetes-related death (P=0.017) than patients assigned to conventional treatment. There were no significant differences in the risk of diabetes-related deaths between those assigned to intensive therapy with metformin and those given sulfonylureas or insulin.2 Metformin-treated patients also had a 36% lower risk of all-cause mortality compared with patients assigned to conventional treatment (P=0.011). This risk reduction with metformin treatment was also greater than in patients treated with a sulfonylurea or insulin (P=0.021).2 10% 0% 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:854-865.

UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT 7.9 Proportion of patients with events UKPDS 15 yrs, mean F/U 10 yrs 0.9 7.0 Conventional (n=411) 35% Intensive (n=951) Metformin (n=342) 30% M vs. C P=0.017 M vs. I P=0.11 I vs. C P=0.029 Standard A1c Between group A1c difference Intensive A1c 7.3 Trial 20% ADVANCE 0.8 6.5 8.4 VADT 1.5 ACCORD, ADVANCE and VADT trials were much shorter than 10 years; likely far too short to show reduction in CVD with intensive glycemic control. This Kaplan-Meier plot shows that patients treated with metformin had a 42% lower risk of diabetes-related death (P=0.017) than patients assigned to conventional treatment. There were no significant differences in the risk of diabetes-related deaths between those assigned to intensive therapy with metformin and those given sulfonylureas or insulin.2 Metformin-treated patients also had a 36% lower risk of all-cause mortality compared with patients assigned to conventional treatment (P=0.011). This risk reduction with metformin treatment was also greater than in patients treated with a sulfonylurea or insulin (P=0.021).2 6.9 10% 7.5 ACCORD 1.1 6.4 0% 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:854-865.

Risk Reduction of Micro- and Macrovascular Complications and Diabetes-related Death in 110 (lean) T2DM patients by Intensive Insulin Therapy over 10 years of the Kumamoto Study. Conventional 9.4% and Intensive 7.1% Between Group HbA1c diff. was 2.3% Mean RRR 6 years 10 years Retinopathy Progression of retinopathy 65%* 67%** Photocoagulation 40%* 77%* Nephropathy Progression of nephropathy 57%* 66%** Neuropathy Clinical neuropathy 58-80%* 64%** Macrovascular Disease Macrovascular complications 46%NS 54%* Diabetes-related death --- 81%* *p<0.05 **p<0.03 Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28:103-117 Wake N, Hisashige A, Katayama T et al. Diabetes Res Clin Pract 2000; 48: 201–210 71

Steno-2 Study Design Conventional Rx Randomized Intensive Rx DM-2 (N = 160) Rx arms: Intensive Multifactorial Management Rx of Glucose, Lipids, BP, etc, per Steno Diabetes Center Conventional Rx per pt’s GP PROBE (Prospective, Randomized, Open, Blinded Endpoint study) Conventional Rx 80 Microvascular Macrovascular Randomized Endpoint examinations 4 years 8 years 80 Intensive Rx Gæde P, et al, NEJM 2003;348:383-393

STENO-2: Total Mortality by Rx Arm Over Time Intensive vs. Conventional HR: ~2 1.0 0.5 year 4 7.8 13.3 50% decrease in total mortality w/ Intensive Rx seen only after >10 years f/u (avg 13.3 y) Gæde P, et al, NEJM. 2008;358:580-591

STENO-2: CVD Events by Rx Arm Over Time ~50% decrease in CVD events w/ Intensive Rx seen only after >7 years f/u (avg 13.3 y) Gæde P, et al, NEJM. 2008;358:580-591 74

Summary and Conclusions: Time-Course of CVD Prevention in DM Glycemic Control— Microvascular benefits: accrue relatively early (<6y in DCCT, UKPDS, Kumamoto, ADVANCE, STENO-2) Macrovascular benefits: Were NOT seen in trials <10y Rx w/ A1c diff. 0.8-1.8% (ACCORD, ADVANCE, VADT, DCCT, UKPDS) WERE seen at 10 y w/ A1c diff 2.3% (Kumamoto) WERE seen at >10 y even after glycemic difference lost— so-called “Metabolic Memory” or “Legacy Effect” (Steno-2, UKPDS-Metformin, UKPDS-10+8.5y-F/U, DCCT-17y-F/U) Total mortality increased at <5 y (Steno-2, ACCORD), but decreased at >10 y (Steno-2-13.3y-F/U, UKPDS-10+8.5yF/U) BP Control—no “Legacy Effect” after end of intervention UKPDS-10+8.5y-F/U) Combined Intensive BP-BG control vs standard BP-BG control reduced CV Mortality and All-cause mortality (ADVANCE), consistent with imperative multifactorial approach (STENO-2) 75