Presentation on theme: "Glucose Lowering in Diabetes Mellitus:"— Presentation transcript:
1Glucose 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 WashingtonEliot A. Brinton, MD—University of UtahPaul Rosenblit, MD—University of California, IrvineModerator:
2Glucose 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, WA2
3ACCORD 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 programDouble 2 by 2 factorial designBuse, JB, et al, AmJCard :21i-33i.
4DSMB Recommendation and NHLBI Decision NHLBI/NIH decision:Discontinue intensive glycemia treatmentTransition all participants to the standard glycemia treatmentNo 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
5Glycemia 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 :21i-33i.
6Glycemia Trial Rationale 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)VACSDM9.3%-56% (-170,10)DIGAMI29% (4,51)UGDP(IVAR)FPGmg/dLmg/dL9% (NS)Observational studies supportiveEach 1% higher A1C associated with 18% greater risk of CVD1CVD-glucose relationship extends into the normal rangeClinical trials inconclusive21. Selvin E, et al. Ann Intern Med. 2004;141:2. Goff DC Jr, et al. Am J Cardiol. 2007;99[suppl]:4i-20i.
7Double 2 X 2 Factorial Design BPLipidIntensive(SBP<120)Standard(SBP<140)Statin + Masked Study DrugStatin + Masked Study DrugIntensiveGlycemia(A1C<6%)11781193138313745128*StandardGlycemia(A1C 7-7.9%)11841178137013915123*2362*2371*2753*2765*10,251*Primary analyses compare the marginals for main effectsBuse, JB, et al, AmJCard :21i-33i.
8Participant Eligibility Stable Type 2 Diabetes for 3+ monthsA1C >7.5% AND <9% (more meds) OR <11% (fewer meds)Age previous CVD events ORAge 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 hypoglycemiaAble/willing to take insulin, do glucose monitoringEligible for BP or Lipid TrialBuse, JB, et al, AmJCard :21i-33i.
9ACCORD Outcomes Primary: Secondary/Other: First occurrence of nonfatal MI OR Nonfatal Stroke OR CV DeathSecondary/Other:Each component of 10Expanded CVD: Revasc & HF HospTotal mortalityMicrovascular (nephropathy, neuropathy, eye)Eye photo substudy (N = 3537)HRQL (N = 2053); Cost (N = 4311)MIND: cognition, brain volume (MRI)Falls/Fractures/BMDBuse, JB, et al, AmJCard :21i-33i.
16Primary Outcome ACCORD Study Group, NEJM 2008 358:2545-2549. 2.29%/yr HR = 0.90( )P = 0.16ACCORD Study Group, NEJM :
17The Question:Can the observed treatment group difference in mortality be explained by the observed post-randomization treatment group difference in severe hypoglycemia?
18Severe Hypoglycemia Requiring Medical Assistance Intensive Group Annual Incidence Rate = 3.3%Standard Group Annual Incidence Rate = 1.0%ACCORD Study Group, NEJM :
19Background: Mortality By Severe Hypoglycemia NeverExperienced a Hypoglycemic EventExperiencedHypoglycemic EventOverallMortalityRates1.2% / year3.3% / yearIntensiveGlycemia1.3% / year2.8% / yearStandardGlycemia1.1% / year4.9% / yearAgain, mortality is higher among participants who had experienced a Severe Hypoglycemic Event, regardless of treatment strategyACCORD Study Group, NEJM :
20Experienced a Hypoglycemic Event Mortality By Treatment Group and Severe HypoglycemiaOverallNeverExperienced a Hypoglycemic EventExperiencedHypoglycemic EventIntensive Glycemia1.4% / year(257 Deaths)1.3% / year(223 Deaths)2.8% / year(34 Deaths)Standard Glycemia1.1% / year(203 Deaths)(186 Deaths)4.9% / year(17 Deaths)HazardRatio(95% CI)1.22 (1.01, 1.46)1.24 (1.02, 1.50)0.54 (030, 0.96)Mortality Higher inIntensive GroupMortality Higher inStandard GroupInteraction P < 0.01ACCORD Study Group, NEJM :
21Conclusions—IAmong 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 groupParticipants who had experienced a severe hypoglycemic event were more likely to dieTrue for both treatment groupsACCORD Study Group, NEJM :
22Conclusions—IIWe 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 groupPremixed Insulin greater mortality, but used more often in Standard Glycemia groupBolus 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 givenApproximately 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 :
23Identifying a “Cause” of the Higher Mortality ACCORD identified a previously unknown harm of a strategy of intensive glucose lowering in high-risk individuals with T2DMACCORD was designed to test a therapeutic strategy, not a specific component of the strategy or specific drug(s); numerous factors differed between the randomized groupsIn a strategy trial, potential causes are difficult, if not impossible, to separate out from other post-baseline factors that differ by groupExample: 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 :
24Conclusion- what caused the difference ? PIt’sTheStrategy (the therapeutic approach to intensive glucose lowering)InThisPopulation (with longstanding T2DM and CVD or CVD RFs)IntentionToTreat analyses (comparing groups based on randomized assignment – the analysis that provides strong evidence of causality)
25Which 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
26Differences Between ACCORD/ADVANCE BASELINE ACCORD ADVANCE# patients , ,140duration DM (yrs)Hx macrovasc. Dz (%)Baseline A1C (%)Interventiontarget A1C (%) < <6.5insulin Rx (%) vs vs. 24TZD Rx (%) vs vs. 11Outcome (intensive vs. standard)Median study end vs. 7.5% 6.4 vs. 7.0%DEATH: any cause vs. 4.0%* 8.9 vs. 9.6%NEJM 2008;358, 2630*P<0.05
30ADVANCE: Secondary Endpoints All-cause mortality: P = NSTotal renal events 11% RR with intensive, P < 0.001Eye events: P = NSCHF, PVD, neuropathy: P = NSADVANCE Collaborative Group, NEJM :
31Candidate 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)
32Big Picture MessagesT1 and T2DM: early meticulous glucose control can prevent microvascular and neuropathic complicationsT1DM: early meticulous glucose control appears to prevent CVD many years laterT2DM: early meticulous glucose control appears to prevent both micro- and macrovascular disease in T2DM
33The Benefit of Early Aggressive Glycemic Control Metabolic memory“Legacy effect”
34Big Picture MessageT2DM: 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
35More Big Picture Messages T1DM: impact of glycemia on microvascular disease not present after 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 A1CImpact of hypoglycemia is not consistent between populations (under 5 year-olds, geriatrics, inpatient)
37My 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: metformin2nd line: SFU, sitagliptin, exenatide, basal insulin (A1C < 9%)3rd line: physiologic insulin therapy10-15 years T2DM AND no CVD:No change from above but this population will be more likely to require insulin to reach A1C target
38Possible Strategy > 15 years T2DM OR known CVD: 7-7.5% A1C Drugs with less risk of hypoglycemiaMetformin, SFU unlikely to be effective with longer durations of DMLittle data for TZDs, exenatide, sitagliptinGreatest risk of hypoglycemia with insulin, but also greatest likelihood of efficacy to consistent A1C levelsLess hypoglycemia with basal insulin alone, but some prandial insulin required as duration of DM and A1C increasesDon’t use basal insulin to replace prandial needs!
39ConclusionThe 4 recent studies do not negate the years of research from other clinical trialsDifferent populations appear to have different A1C targetsIt 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 usGeneral: hypoglycemia, weight gain, pregnancy, costSpecific: GI tolerability, edema, bone fx, increase CVD risk (?)
40ConclusionInsulin is always an option, is under-utilized, and needs to be used in a physiologic manner in patients with severe insulin deficiencyIn 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.
41Eliot 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 LipidologyAssociate Professor, University of Utah Director, Metabolism Section of Cardiovascular Genetics Salt Lake City, UT
42VADT: Design Subject Inclusion: DM-2 on insulin or unresponsive to maximal doses oral agentsCentral 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 ULNN=1791 (20 centers)Prospective, randomized study of:Intensive vs. standard glycemic Rx, yearsBackground good diet & lifestyle + Rx BP & lipids (both arms)1o endpoint: CVD compositeGet to the POINTTell what will tellPowered at 85% to detect...Abraira, C, et al, J Diab. Complic, 2003; 17: 314
43VADT: Design (cont’d) Primary outcome Composite of: MI, CVA, CVD Death, CHF, PCI, CABG, “Inoperable” CAD, LE revascularization or amputation for ischemiaSecondary outcomesTotal mortalityAnginaTIAClaudicationCritical limb ischemiaRetinopathyNephropathyNeuropathyQuality of lifeCognitive functionCost-effectivenessGet to the POINTTell what will tellPowered at 85% to detect...Abraira, C, et al, J Diab. Complic, 2003; 17: 314
44VADT: Baseline Subject Characteristics (similar in both arms) Sex: 97% maleAge: yDM Duration: yBMI: kg/m2A1c: %RaceNon-Hispanic, White: 62%African-American: 17%Hispanic: 16%Other: 5%Smoking historyCurrent: 17%Former: 55%Never: 28%Abraira, C. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
45VADT: Glycemic Rx and Results A1c Goal by Study ArmIntensive: <7%Standard: 8-9%Method (same in both Rx arms):Metformin (BMI>27) or glimepiride (BMI<27)RosiglitazoneInsulinOther oral agentsToolbox: add any other drugs to get to Rx goalsOn-study A1c by Study ArmIntensive: 6.9%Standard: 8.4%Abraira, C, et al, J Diab. Complic, 2003; 17: 314
46VADT: Primary Endpoint TreatmentStandardIntensiveNIncidence%P-value89926329.389223125.90.11Non-significant trend towards 12% decrease inCVD (composite) with intensive glycemic controlDuckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
47VADT: Antiplatelet/Anticoagulant, Statins and Cigarette Use (%) Cigarette SmokingAbraira, C. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
48VADT: On-Study LDL-C (Median/IQR mg/dL) ~30% ↓in LDL-CAbraira, C. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
49VADT: On-Study HDL-C (Median/IQR mg/dL) ~18% ↑in HDL-CAbraira, C. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
50VADT: On-Study TG (Median/IQR mg/dL) ~21% ↓in TGAbraira, C. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
51Predictors of Initial 1o Outcome Event (Treatment by Duration Interaction) VariableHRLower CIUpper CIp-valuePrior CV event3.302.503.69<.0001Age1.331.191.49HDL0.830.760.91HbA1c1.091.021.160.01Hypoglycemia2.071.143.770.02DM Duration-Std. Rx1.010.990.5DM Duration- Intens. Rx1.031.05Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
52CVD Hazard Ratio Intensive/Standard Rx VADT: Intensive Glycemia Rx Beneficial if Started Early (DM Duration <15 years)No correlationin Std. Rx groupCVD Hazard Ratio Intensive/Standard Rxp<0.0001DM Duration (years)Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy. Accessed July 200852
53VADT: Severe Hypoglycemia NIncidence%pImpaired ConsciousnessStd. Rx899798.8<0.01Intens. Rx89217820.0Loss of Consciousness394.39110.2Severe Hypoglycemia*879.718821.1*Either impaired or total loss of consciousness. Some subjects had both.Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
54Predictors of All-Cause Mortality VariableHRLower CIUpper CIp-valuePrior event1.901.402.58<.0001Age2. 412.002.91Smoker1.701.162.480.006BaselineHbA1c1.171.061.290.002Hypoglycemia* (Std Rx)18.104.22.168.001Hypoglycemia (Intens. Rx)1.280.404.050.7*Also predicted primary endpoint (CVD composite) and CVD death.Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy.
55Effect of Rosiglitazone on Time to CVD Death (Non-randomized Rx) Veterans Affairs Diabetes TrialEffect of Rosiglitazone on Time to CVD Death(Non-randomized Rx)UnadjustedAdjusted: baseline*Adjusted: baseline and time covariates**8 mgHazard Ratio:0.51.01.54 mg*Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP**Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smokerIn the VADT, it was better to be on Rosiglitazone than not.Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy. Accessed July 200855
56Veterans Affairs Diabetes Trial Effect of Rosiglitazone on Time to MI (Non-randomized Rx)UnadjustedAdjusted: baseline*Adjusted: baseline and time covariates**8 mgHazard Ratio:0.51.01.54 mg*Baseline covariates: age, baseline insulin use, prior event, smoker, baseline SBP**Baseline and time-dependent covariates: age, baseline insulin Rx, prior CVD, smokerIn the VADT, it was better to be on Rosiglitazone than not.Duckworth, W. ADA Scientific Sessions, June Pre-publication CONFIDENTIAL do not copy. Accessed July 200856
57VADT: 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 RxHypoglycemia 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.
58Are ‘Blood Glucose Control’ Trials Less than 10 years Duration Long Enough to Show CVD Benefit?: Time to Benefit and “Legacy Effect” of Lower GlycemiaPaul D. Rosenblit MD, PhD, FACE Private Solo PracticeEndocrinology, Diabetes and Metabolism, andClinical Professor of Medicine Univ. of California, Irvine School of Medicine
59DCCT/EDIC: Lower Glycemia in DM-1 Diabetes Control & Complications Trial (Randomized Intervention) / Epidemiology of Diabetes Interventions & Complications (Observational F/U)ConventionalIntensive68101234571234567891011NormalConventionalIntensive8.9%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 6.05DCCT Study yrEDIC yrAdapted from DCCT Research Group. N Engl J Med 1993;329: DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:
60Conventional 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 treatmentMACE (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 questionThe DCCT/EDIC set out to investigate the benefits of intensive insulin therapy in patients with type 1 diabetes mellitus, as compared with conventional therapy 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 treatmentNo. at RiskYears since entryIntensive705686640118Conventional72169463796DCCT/EDIC Study Research Group, N Engl J Med 2005; 353:
61UKPDS: Lower Glycemia in DM-2 with Intensive Intervention Over 10 years HbA1c was 7·0% (6·2–8·2) in the intensive groupcompared with 7·9% (6·9–8·8) in the conventional group9Average between group A1c difference = 0.9%Conventional8Median A1c (%)Intensive (Sulfonylurea or Insulin)7Shown 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.1Within 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.163691215Years from randomizationUKPDS Group. Lancet. 1998;352:
62After 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-UpRelative risk* (95% CI)Reduced Increased risk riskRR P valueAny diabetes-related endpointDiabetes-related deathsAll-cause mortalityMyocardial infarctionStrokeMicrovascularPatients 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).1For 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.1Favors Favors Intensive Conventional*vs. conventional policy.Microvascular, NOT Macrovascular, events were reduced in UKPDS trialUKPDS Group. Lancet. 1998;352:
63UK Prospective Diabetes Study and Long-Term F/U Interventional Trial (Randomized, Blinded),N=5,102, newly-diagnosed DM-2 (recruited )Median randomized follow-up 10 y (6-20 y)10-y Post-Trial Monitoring, *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:
64UKPDS Post-Trial Follow-Up A1c UKPDS results presentedMean (95%CI)UKPDS HbA1c diff. 0.9% end of trialUKPDS website--Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
65UKPDS “Legacy Effect” of Earlier Glucose Control with Insulin or Sulfonylurea Interv F/UAggregate EndpointAny diabetes related endpoint RRR: 12% 9%P:Microvascular disease RRR: 25% 24%P:Myocardial infarction RRR: 16% 15%P:All-cause mortality RRR: 6% 13%P:RRR = Relative Risk Reduction, P = Log RankHolman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
66UKPDS: “Legacy Effect” of Earlier Glucose Control with Metformin in Overweight Patients Interv F/UAggregate EndpointAny diabetes related endpoint RRR: 32% 21%P:Microvascular disease RRR: 29% 16%P:Myocardial infarction RRR: 39% 33%P:All-cause mortality RRR: 36% 27%P:RRR = Relative Risk Reduction, P = Log RankHolman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
67UKPDS Post-Trial Follow-up Blood Pressure UKPDS results presentedMean (95%CI)UKPDS website--Holman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
68UKPDS: No “Legacy Effect” of Earlier BP Control Interv F/UAggregate EndpointAny diabetes related endpoint RRR: 24% 7%P:Microvascular disease RRR: 37% 16%P:Myocardial infarction RRR: 21% 10%P:All-cause mortality RRR: 18% 11%P:RRR = Relative Risk Reduction, P = Log RankHolman RR, Paul SK, Bethel MA et al. NEJM 2008;359:
69UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT7.9Proportion of patients with eventsUKPDS 15 yrs, mean F/U 10 yrs0.97.0Conventional (n=411)35%Intensive (n=951)Metformin (n=342)30%M vs. C P=0.017M vs. I P=0.11I vs. C P=0.029Standard A1cBetween groupA1c differenceIntensive A1cTrial20%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.2Metformin-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).210%0%3691215Years from randomizationUKPDS Group. Lancet. 1998;352:
70UKPDS CVD (Diabetes-Related Deaths) and Trial Duration at Curve Separation: What are your expectations for ACCORD, ADVANCE and VADT7.9Proportion of patients with eventsUKPDS 15 yrs, mean F/U 10 yrs0.97.0Conventional (n=411)35%Intensive (n=951)Metformin (n=342)30%M vs. C P=0.017M vs. I P=0.11I vs. C P=0.029Standard A1cBetween groupA1c differenceIntensive A1c7.3Trial20%ADVANCE0.86.58.4VADT1.5ACCORD, 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.2Metformin-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).26.910%7.5ACCORD1.16.40%3691215Years from randomizationUKPDS Group. Lancet. 1998;352:
71Risk 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 RRR6 years yearsRetinopathyProgression of retinopathy %* %**Photocoagulation %* %*NephropathyProgression of nephropathy %* %**NeuropathyClinical neuropathy %* %**Macrovascular DiseaseMacrovascular complications %NS %*Diabetes-related death %**p< **p<0.03Ohkubo Y, Kishikawa H, Araki E, et al. Diabetes Res Clin Pract 1995;28:Wake N, Hisashige A, Katayama T et al. Diabetes Res Clin Pract 2000; 48: 201–21071
72Steno-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 CenterConventional Rx per pt’s GPPROBE (Prospective, Randomized, Open, Blinded Endpoint study)Conventional Rx80MicrovascularMacrovascularRandomizedEndpoint examinations4 years8 years80Intensive RxGæde P, et al, NEJM 2003;348:
73STENO-2: Total Mortality by Rx Arm Over Time Intensive vs. Conventional HR: ~year50% 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:
74STENO-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;358:74
75Summary 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 % (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 y-F/U, DCCT-17y-F/U)Total mortality increased at <5 y (Steno-2, ACCORD), but decreased at >10 y (Steno y-F/U, UKPDS yF/U)BP Control—no “Legacy Effect” after end of intervention UKPDS y-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