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Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease CVD Mortality and/or Events? Presenters: Jeff Probstfield, MD—University of Washington.

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Presentation on theme: "Glucose Lowering in Diabetes Mellitus: Does it Increase or Decrease CVD Mortality and/or Events? Presenters: Jeff Probstfield, MD—University of Washington."— Presentation transcript:

1 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: Eliot A. Brinton, MD—University of Utah

2 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

3 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 ACCORD Trial Overall Goal Buse, JB, et al, AmJCard 2007 99:21i-33i.

4 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) DSMB Recommendation and NHLBI Decision

5 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%)? Glycemia Trial Research Question Buse, JB, et al, AmJCard 2007 99:21i-33i.

6 Observational studies supportive –Each 1% higher A1C associated with 18% greater risk of CVD 1 –CVD-glucose relationship extends into the normal range Clinical trials inconclusive 2 StudyMean 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) Kumamoto7.1%9.4%46% (NS) VACSDM7.1%9.3%-56% (-170,10) DIGAMI7.1%7.9%29% (4,51) UGDP(IVAR)FPG 130-146 mg/dL FPG 170-186 mg/dL 9% (NS) 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. Glycemia Trial Rationale

7 Intensive Glycemia (A1C<6%) 5128* Standard Glycemia (A1C 7-7.9%) 5123* Lipid Statin + Masked Study Drug BP Intensive (SBP<120) Standard (SBP<140) 2765*2753* 2362* 2371* 11781193 11781184 1374 1391 1370 1383 10,251 *Primary analyses compare the marginals for main effects Double 2 X 2 Factorial Design Buse, JB, et al, AmJCard 2007 99:21i-33i.

8 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 Participant Eligibility Buse, JB, et al, AmJCard 2007 99:21i-33i.

9 Primary: OR –First occurrence of nonfatal MI OR Nonfatal Stroke OR CV Death Secondary/Other: –Each component of 1 0 –Expanded CVD: 1 0 + 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 ACCORD Outcomes Buse, JB, et al, AmJCard 2007 99:21i-33i.

10 Intensive Rx Goal Standard Rx Goal A1C Distribution

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

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

13 1.41%/yr 1.14%/yr HR = 1.22 (1.01-1.46) P = 0.04 All Cause Mortality ACCORD Study Group, NEJM 2008 358:2545-2549.

14 Intensive N (%) Standard N (%)HR (95% CI)P Primary352 (6.86)371 (7.23)0.90 (0.78-1.04)0.16 Secondary Mortality257 (5.01)203 (3.96)1.22 (1.01-1.46)0.04 Nonfatal MI186 (3.63)235 (4.59)0.76 (0.62-0.92)0.004 Nonfatal Stroke67 (1.31)61 (1.19)1.06 (0.75-1.50)0.74 CVD Death135 (2.63)94 (1.83)1.35 (1.04-1.76)0.02 CHF152 (2.96)124 (2.42)1.18 (0.93-1.49)0.17 Primary & Secondary Outcomes ACCORD Study Group, NEJM 2008 358:2545-2549.

15 Intensive N (%) Standard N (%)HR (95% CI)P Primary352 (6.86)371 (7.23)0.90 (0.78-1.04)0.16 Secondary Mortality257 (5.01)203 (3.96)1.22 (1.01-1.46)0.04 Nonfatal MI186 (3.63)235 (4.59)0.76 (0.62-0.92)0.004 Nonfatal Stroke67 (1.31)61 (1.19)1.06 (0.75-1.50)0.74 CVD Death135 (2.63)94 (1.83)1.35 (1.04-1.76)0.02 CHF152 (2.96)124 (2.42)1.18 (0.93-1.49)0.17 Primary & Secondary Outcomes ACCORD Study Group, NEJM 2008 358:2545-2549.

16 2.29%/yr 2.11%/yr HR = 0.90(0.78-1.04) P = 0.16 Primary Outcome ACCORD Study Group, NEJM 2008 358:2545-2549.

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

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

19 Never Experienced a Hypoglycemic Event Experienced Hypoglycemic Event Overall Mortality Rates 1.2% / year3.3% / year Again, mortality is higher among participants who had experienced a Severe Hypoglycemic Event, regardless of treatment strategy Background: Mortality By Severe Hypoglycemia Intensive Glycemia 1.3% / year2.8% / year Standard Glycemia 1.1% / year4.9% / year ACCORD Study Group, NEJM 2008 358:2545-2549.

20 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) 1.1% / year (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 By Treatment Group and Severe Hypoglycemia Mortality Higher in Intensive Group Mortality Higher in Standard Group Interaction P < 0.01 ACCORD Study Group, NEJM 2008 358:2545-2549.

21  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 Conclusions—I ACCORD Study Group, NEJM 2008 358:2545-2549.

22 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. Conclusions—II ACCORD Study Group, NEJM 2008 358:2545-2549.

23 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) Identifying a “Cause” of the Higher Mortality ACCORD Study Group, NEJM 2008 358:2545-2549.

24 ITSITPITTITSITPITT 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) Conclusion- what caused the difference ?

25 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

26 Differences Between ACCORD/ADVANCE BASELINE ACCORDADVANCE # 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. 5541 vs. 24 TZD Rx (%) 92 vs. 5817 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

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

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

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

30 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.

31 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)

32 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

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

34 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

35 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)

36 SO WHAT A1C TARGETS?

37 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% –1 st line: metformin –2 nd line: SFU, sitagliptin, exenatide, basal insulin (A1C < 9%) –3 rd 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

38 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!

39 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 (?)

40 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.

41 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

42 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) 1 o endpoint: CVD composite Abraira, C, et al, J Diab. Complic, 2003; 17: 314

43 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 Abraira, C, et al, J Diab. Complic, 2003; 17: 314 VADT: Design (cont’d)

44 Sex: 97% male Age: 60.4 + 9.5 y DM Duration: 11.5 + 7.7 y BMI: 31.3 + 4.6 kg/m 2 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% VADT: Baseline Subject Characteristics (similar in both arms) Abraira, C. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

45 VADT: Glycemic Rx and Results A1c Goal by Study Arm Intensive: <7% Standard: 8-9% Method (same in both Rx arms): 1.Metformin (BMI>27) or glimepiride (BMI<27) 2.Rosiglitazone 3.Insulin 4.Other oral agents 5.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

46 VADT: Primary Endpoint Non-significant trend towards 12% decrease in CVD (composite) with intensive glycemic control Treatment StandardIntensive N Incidence %N %P-value 89926329.389223125.90.11 Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

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

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

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

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

51 Predictors of Initial 1 o Outcome Event (Treatment by Duration Interaction) VariableHRLower CIUpper CIp-value Prior CV event3.302.503.69<.0001 Age1.331.191.49<.0001 HDL0.830.760.91<.0001 HbA 1 c1.091.021.160.01 Hypoglycemia2.071.143.770.02 DM Duration- Std. Rx 1.010.991.020.5 DM Duration- Intens. Rx 1.031.021.05<.0001 Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

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

53 NIncidence%p Impaired Consciousness Std. Rx899798.8 <0.01 Intens. Rx89217820.0 Loss of Consciousness Std. Rx899394.3 <0.01 Intens. Rx8929110.2 Severe Hypoglycemia* Std. Rx899879.7 <0.01 Intens. Rx89218821.1 VADT: Severe Hypoglycemia Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. *Either impaired or total loss of consciousness. Some subjects had both.

54 Predictors of All-Cause Mortality VariableHRLower CIUpper CIp-value Prior event1.901.402.58<.0001 Age2. 412.002.91<.0001 Smoker1.701.162.480.006 Baseline HbA 1 c 1.171.061.290.002 Hypoglycemia* (Std Rx) 5.92.116.10.001 Hypoglycemia (Intens. Rx) 1.280.404.050.7 *Also predicted primary endpoint (CVD composite) and CVD death. Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy.

55 Veterans Affairs Diabetes Trial Effect of Rosiglitazone on Time to CVD Death (Non-randomized Rx) *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. Unadjusted Adjusted: baseline* Adjusted: baseline and time covariates** 8 mg Hazard Ratio:0.51.01.5 4 mg 8 mg 4 mg 8 mg 4 mg Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008

56 In the VADT, it was better to be on Rosiglitazone than not. Unadjusted Adjusted: baseline* Adjusted: baseline and time covariates** 8 mg Hazard Ratio:0.51.01.5 4 mg 8 mg 4 mg 8 mg 4 mg Duckworth, W. ADA Scientific Sessions, June 2008. Pre-publication CONFIDENTIAL do not copy. http://www.diabetes.org/diabetesconnect/brousethe2008webcastcollection. Accessed July 2008 Veterans Affairs Diabetes Trial Effect of Rosiglitazone on Time to MI (Non-randomized Rx) *Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP **Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smoker

57 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.

58 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

59 DCCT Study yr 012345678910 5 6 7 8 9 11 Normal Conventional Intensive A1c (%) 8.9% 7.1% Normal  6.05 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 EDIC yr DCCT/EDIC: Lower Glycemia in DM-1 Diabetes Control & Complications Trial (Randomized Intervention) / Epidemiology of Diabetes Interventions & Complications (Observational F/U) 7.8% 7.9% mean 8.2% mean 8.0% Between group A1c difference 1.8%

60 Years since entry MACE (NF MI, CVA, or CVD death) Conventional treatment Intensive treatment DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:2643-53. Intensive705686640118 Conventional72169463796 No. at Risk Intervention ----------------Follow-up------------------  ↓ 57% RRR p=0.02) Lower Glycemia in DM-1 Decreases CVD But Benefits are Delayed (DCCT-EDIC)

61 UKPDS: Lower Glycemia in DM-2 with Intensive Intervention UKPDS Group. Lancet. 1998;352:837-853. 0 6 7 8 9 03691215 Median A 1c (%) Years from randomization Conventional Intensive (Sulfonylurea or Insulin) Average between group A1c difference = 0.9% 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

62 UKPDS: Aggregate Clinical Endpoints in Glucose Control Study with Between Group HbA1c Difference of Only 0.9% FavorsFavors Intensive Conventional UKPDS Group. Lancet. 1998;352:837-853 RRP value Any diabetes-related endpoint0.880.029 Diabetes-related deaths0.900.34 All-cause mortality0.940.44 Myocardial infarction0.840.052 Stroke1.110.52 Microvascular0.750.0099 Relative risk* (95% CI) ReducedIncreased 0.5 risk 1 risk 2 *vs. conventional policy. After Mean 10-Years’ Follow-Up Microvascular, NOT Macrovascular, events were reduced in UKPDS trial

63 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) Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359: *no attempts to maintain previously assigned therapies.

64 UKPDS Post-Trial Follow-Up A 1c 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 HbA1c diff. 0.9% end of trial

65 Interv. F/U Aggregate Endpoint -1997-2007 Any diabetes related endpointRRR:12%9% P: 0.029 0.040 Microvascular diseaseRRR: 25%24% P: 0.00990.001 Myocardial infarctionRRR:16%15% P: 0.0520.014 All-cause mortalityRRR:6%13% P: 0.440.007 RRR = Relative Risk Reduction, P = Log Rank UKPDS “Legacy Effect” of Earlier Glucose Control with Insulin or Sulfonylurea Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

66 Interv. F/U Aggregate Endpoint -1997-2007 Any diabetes related endpointRRR:32%21% P: 0.0023 0.013 Microvascular diseaseRRR: 29%16% P: 0.190.31 Myocardial infarctionRRR:39%33% P: 0.0100.005 All-cause mortalityRRR:36%27% P: 0.0110.002 RRR = Relative Risk Reduction, P = Log Rank UKPDS: “Legacy Effect” of Earlier Glucose Control with Metformin in Overweight Patients Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

67 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:

68 UKPDS: No “Legacy Effect” of Earlier BP Control Interv. F/U Aggregate Endpoint -1997-2007 Any diabetes related endpointRRR:24%7% P: 0.0046 0.31 Microvascular diseaseRRR: 37%16% P: 0.00920.17 Myocardial infarctionRRR:21%10% P: 0.130.35 All-cause mortalityRRR:18%11% P: 0.170.18 RRR = Relative Risk Reduction, P = Log Rank Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:

69 0% 10% 20% 30% 35% 03691215 Proportion of patients with events Years from randomization Conventional (n=411) Intensive (n=951) Metformin (n=342) UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT M vs. I P=0.11 M vs. C P=0.017 UKPDS Group. Lancet. 1998;352:854-865. Trial Standard A1c Between group A1c difference Intensive A1c 7.9 7.0 0.9 I vs. C P=0.029 UKPDS 15 yrs, mean F/U 10 yrs

70 0% 10% 20% 30% 35% 03691215 Proportion of patients with events Years from randomization Conventional (n=411) Intensive (n=951) Metformin (n=342) UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT M vs. I P=0.11 M vs. C P=0.017 UKPDS Group. Lancet. 1998;352:854-865. VADT ADVANCE ACCORD ACCORD, ADVANCE and VADT trials were much shorter than 10 years; likely far too short to show reduction in CVD with intensive glycemic control. 7.5 7.3 6.5 8.4 6.4 6.9 1.1 1.5 0.8 Trial Standard A1c Between group A1c difference Intensive A1c 7.9 7.0 0.9 I vs. C P=0.029 UKPDS 15 yrs, mean F/U 10 yrs

71 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% 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%* Wake N, Hisashige A, Katayama T et al. Diabetes Res Clin Pract 2000; 48: 201–210 Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28:103-117 Mean RRR *p<0.05 **p<0.03 6 years 10 years

72 Steno-2 Study Design Conventional Rx Intensive Rx Endpoint examinations MicrovascularMacrovascular 4 years8 years 80 Randomized 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) Gæde P, et al, NEJM 2003;348:383-393

73 STENO-2: Total Mortality by Rx Arm Over Time Gæde P, et al, NEJM. 2008;358:580-591 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)

74 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)

75 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 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)


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