Tight Glycemic Control in the Prevention of Cardiovascular Disease
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Tight Glycemic Control in the Prevention of Cardiovascular Disease

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Lecture at the Diabetes Philippines Vascular Course

Lecture at the Diabetes Philippines Vascular Course

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    Tight Glycemic Control in the Prevention of Cardiovascular Disease Tight Glycemic Control in the Prevention of Cardiovascular Disease Presentation Transcript

    • Glucose lowering for the prevention of CVD: Positive, Negative or Neutral Iris Thiele Isip Tan MD, FPCP, FPSEM Clinical Associate Professor, University of the Philippines College of Medicine Section of Endocrinology, Diabetes & Metabolism Department of Medicine, Philippine General Hospital
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Who will benefit UKPDS from tight glycemic control? Objective To determine whether improved glucose control would prevent complications Newly diagnosed type 2 diabetes (n=3867) Median age 54 y UKPDS Group, Lancet 1998;352: 837-53
    • Newly diagnosed diabetes UKPDS Newly diagnosed diabetes FastingFasting plasma glucose >6mmoll plasma glucose >6 mmol/L –1 ‘Prudentdiet’ ‘Prudent diet’ for 3–4 months for 3-4 mos Design >6 mmol/L >6mmoll–1 <6 mmol/L !6mmoll –1 >6 and <15 mmol/L >6 and !15mmoll–1 >15 mmol/L –1 >15mmoll Diet satisfactory Diet satisfactory Main Main randomization Primary dietfailure Primary diet failure randomization randomization randomization If ifbecomes becomes –1 >6 mmol/L >6mmoll Figure adapted from King et al. Conventional policy Conventional policy Intensive policy Intensive policy Br J Clin Pharmacol, 48:643-48 target<15mmoll target <15 mmol/L target <6 <6mmoll target mmol/L –1 –1 Diet only Diet only Sulphonylurea Sulphonylurea Insulin Insulin Metformin Metformin (obese patients only) (obese patients only) Figure 3 Design of UKPDS.
    • UKPDS Endpoints any diabetes-related endpoint diabetes-related death all-cause mortality UKPDS Group, Lancet 1998;352: 837-53
    • UKPDS Results 0 -12 -25 -33 -21 -16 % Relative Risk Reduction -10 p=0.03 p=0.052 -20 p=0.02 p<0.01 -30 p<0.01 -40 10-year follow-up median HbA1c Intensive 7.0% (6.2-8.2%) Conventional 7.9% (6.9-8.8%) -50 Any DM endpoint Microvascular complications Microalbuminuria at 12 yrs Retinopathy Myocardial Infarction
    • Fatal and non-fatal myocardial infarction Fatal and n 10 Hazard ratio P<0.0001 P=0.035 1 14% decrease per 1% reduction in HbA1c 0.5 5 6 7 8 9 10 Microvascular end points Cataract ex 10 Updated mean HbA1c (%) azard ratio P<0.0001 P<0.0001 Stratton et al, BMJ 2000; 321:405-12
    • e- ne 80 Adjusted incidence per 1000 person years (%) to Myocardial infarction Myocardial infarction he Microvascular end points als Microvascular end points At near normal A1c of he 60 Risk of MI 2-3x nt that of micro- ow he vascular endpoint est a 40 %. g- an to % 20 in Adjusted for age, sex and ethnic of group, expressed for white men ce aged 50-54 years at diagnosis ng and with mean duration of by diabetes at 10 years 0 a 5 6 7 8 9 10 11 as Updated mean haemoglobin A1c concentration (%) rd on Fig 2 Incidence rates and 95% confidence intervals for myocardial Stratton et al, BMJ 2000; 321:405-12 a infarction and microvascular complications by category of updated
    • Who will benefit No benefit from tight in UKPDS? glycemic control? Underpowered to detect reduction in CVD
    • Who will benefit No benefit from tight in UKPDS? glycemic control? Too late to reverse macrovascular complications
    • Vascular disease begins early ... Insulin resistance precedes overt hyperglycemia or diabetes LaSalle JR. Hosp Physician 2005 Plante & Nadler, Seminars Cardiothoracic Vascular Anes 2003; 7(3):295-310
    • Vascular disease begins early ... Insulin resistance precedes overt hyperglycemia or diabetes 2-fold increased risk of CVD in IGT LaSalle JR. Hosp Physician 2005 Plante & Nadler, Seminars Cardiothoracic Vascular Anes 2003; 7(3):295-310
    • Vascular disease begins early ... Insulin resistance precedes overt hyperglycemia or diabetes 2-fold increased risk of CVD in IGT LaSalle JR. Hosp Physician 2005 Plante & Nadler, Seminars Cardiothoracic Newly-diagnosed diabetics have Vascular Anes 2003; 7(3):295-310 vascular disease at presentation
    • Fatal and non-fatal myocardial infarction Fatal and non-fatal stroke Hazard ratio 10 P<0.0001 Macrovascular disease P=0.035 occurs at a lower 10 glucose threshold; %) influenced by components of MetSyn 1 14% decrease per 1% 12% decrease per 1% reduction in HbA1c reduction in HbA1c 0.5 Microvascular end points Cataract extraction 10 Hazard ratio P<0.0001 Microvascular but not P<0.0001 macrovascular disease clearly associated with hyperglycemia 1 k 37% decrease per 1% 19% decrease per 1% , reduction in HbA1c reduction in HbA1c 0.5 , 5 6 7 8 9 10 Plante & Nadler, Seminars Cardiothoracic Vascular Anes 2003; 7(3):295-310 n Amputation or death from
    • Who will benefit No benefit from tight in UKPDS? glycemic control? Cardiovascular disease in diabetes is multifactorial in origin
    • Dyslipidemia Hypertension ACE Inhibitors Angiotensin Receptor Blockers Statins !-Blockers Fibric Acid Derivatives ATHEROSCLEROSIS Calcium Channel Blockers Thiazolidinediones? Diuretics Hyperglycemia Platelet Activation Insulin Resistance and Aggregation Insulin Metformin Thiazolidinediones Aspirin Clopidogrel Sulfonylureas Ticlopidine Nonsulfonylurea Secretagogues Beckman et al, JAMA 2002;287:2570-81
    • Steno-2 Multifactorial intervention and cardiovascular disease Objective To compare the effect of a targeted, intensified, multifactorial intervention vs conventional treatment of modifiable CV risk factors Type 2 diabetes with microalbuminuria Mean age 55.1 y Mean ff-up 7.8 y (n=160) Gaede et al, NEJM 2003;348:383-93
    • Steno-2 Endpoint Composite of CV death, nonfatal MI, nonfatal stroke, revascularization and amputation Gaede et al, NEJM 2003;348:383-93
    • Percentage of patients who reached intensive treatment goals at a mean of 7.8 years 80 P<0.001 P=0.21 70 60 P=0.19 50 Patients (%) P=0.001 40 Intensive 30 Conventional 20 P=0.06 10 0 Glycosylated Cholesterol Triglycerides Systolic BP Diastolic BP Hemoglobin <175 mg/dl <150 mg/dl <130 mm Hg <80 mm Hg <6.5% Gaede et al, NEJM 2003;348:383-93
    • A 60 P=0.007 Primary Composite End Point (%) 50 Conventional therapy Conventional therapy 40 30 20 Intensive therapy Intensive therapy 10 Lower risk of CVD HR 0.47 (95%CI 0.24,0.73) 0 0 12 24 36 48 60 72 84 96 Months of Follow-up No. at Risk Conventional 80 72 70 63 59 50 44 41 13 therapy Intensive 80 78 74 71 66 63 61 59 19 therapy Gaede et al, NEJM 2003;348:383-93
    • Who will benefit No benefit from tight in UKPDS? glycemic control? Treatment was adjusted to FBG only (not PPBG)
    • Relative contribution of postprandial and fasting glucose to HbA1c WHO criteria FPG < 6.0 mmol/L Postprandial glucose exposure Fasting hyperglycaemia 100 90 p=0.004 p<0.001 80 69.8 % contribution 70 54.3 60 49.6 50.4 45.7 50 40 30.2 30 20 10 0 < 7.0% – 7.1%-9.0% > 9.0% E HbA1C groups IN Peter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14
    • Who will benefit No benefit from tight glycemic control? in UKPDS? Treatment was adjusted to FBG only (not PPBG) Kumamoto study (n=110) Intensive insulin regimen vs conventional treatment x 8 years Titration based on FBG, HbA1c and PPBG Nonsignificant ~50% reduction in macrovascular complications Peter & Rees, Br J Diabetes Vasc Dis 2008;8:8-14
    • Who will benefit ACCORD from tight glycemic control? Objective To determine if 3 separate strategies can reduce CV events Intensive therapy to target normal A1c levels (<6.0%) vs standard therapy to target A1c 7.0-7.9% Therapy to target SBP <120 mm Hg Type 2 diabetes vs <140 mm Hg Mean age 62.2 y Addition of fenofibrate vs placebo in Median DM duration 10 y patients on statin therapy with 35% had previous CVD optimal LDL-C 35% already on insulin (n=10,251) ACCORD Group, NEJM 2008;358: 2545-59
    • ACCORD Endpoint Composite of nonfatal MI, nonfatal stroke or death from CV causes ACCORD Group, NEJM 2008;358: 2545-59
    • 25 median HbA1c at 1 y Standard 7.5% 20 n = 371 Intensive 6.4% Standard therapy 15 10 HR 0.90 (95%CI 0.78,1.04) p=0.16 Intensive therapy n = 352 5 0 0 1 2 3 4 5 6 Intensive therapy 5128 4843 4390 2839 1337 475 448 Standard therapy 5123 4827 4262 2702 1186 440 395 ACCORD Group, NEJM 2008;358: 2545-59
    • Total 10,251 723 Previous cardiovascular event 0.04 No 6,643 330 Yes 3,608 393 Sex 0.74 Female 3,952 212 Male 6,299 511 Age at baseline 0.65 <65 yr 6,779 383 ≥65 yr 3,472 340 Glycated hemoglobin at baseline 0.03 ≤8.0% 4,868 284 >8.0% 5,360 438 Race 0.29 Nonwhite 3,647 222 White 6,604 501 0.6 1.0 1.4 ACCORD Group, NEJM 2008;358: 2545-59
    • 25 20 15 n = 257 10 HR 1.22 (95%CI 1.01,1.46) Intensive therapy p=0.04 5 Standard therapy n = 203 0 0 1 2 3 4 5 6 Intensive therapy 5128 4972 4803 3250 1748 523 506 Standard therapy 5123 4971 4700 3180 1642 499 480 ACCORD Group, NEJM 2008;358: 2545-59
    • Who will benefit No benefit from tight in ACCORD? glycemic control? Amount of HbA1c reduction achieved relative to baseline level Rapidity with which HbA1c was achieved or actual HbA1c itself Treatments used or sequence of treatments used Presence of unrecognized hypoglycemia Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72
    • Who will benefit ADVANCE from tight glycemic control? Intensive glucose Standard glucose control control (Gliclazide MR-based) Target A1c based Target A1c <6.5% on local guidelines Perindopril- Perindopril- Indapamide-based Indapamide-based Routine BP lowering Routine BP lowering Intensive glucose Standard glucose control control Type 2 diabetes (Gliclazide MR-based) Target A1c based Mean age 66 y Target A1c <6.5% on local guidelines Mean DM duration 8 y 37% from Asia Usual BP lowering therapy Usual BP lowering therapy 32% with history of macrovascular disease (n=11,140) ADVANCE Collaborative Group, NEJM 2008;358:2560-72
    • ADVANCE Endpoints Composites of major macrovascular and microvascular events jointly and separately Macrovascular events Death from CV causes, nonfatal MI or nonfatal stroke ADVANCE Collaborative Group, NEJM 2008;358:2560-72
    • 25 median HbA1c at 5 y Standard 7.3% 20 Intensive 6.5% 15 Standard control 10 HR 0.94 Intensive (95%CI 0.84,1.06) control 5 P=0.32 0 0 6 12 18 24 30 36 42 48 54 60 66 Intensive 5570 5494 5428 5338 5256 5176 5097 5005 4927 4396 2071 486 Standard 5569 5486 5413 5330 5237 5163 5084 4995 4922 4385 2108 509 ADVANCE Collaborative Group, NEJM 2008;358:2560-72
    • HR 0.93 (95%CI 0.83,1.06) ADVANCE Collaborative Group, NEJM 2008;358:2560-72
    • No benefit in ADVANCE? Inadequate statistical power to detect reduction in macrovascular Who will benefit events from tight Annual rate of 2.2% lower than glycemic control? anticipated rate of 3% (greater use of statins, BP-lowering drugs and anti-platelet agents) ADVANCE Collaborative Group, NEJM 2008;358:2560-72
    • Who will benefit VADT from tight glycemic control? Objective To determine effects of intensive glycemic control (target HbA1c <6%) vs standard control (HbA1c 8% to 9%) on CV outcomes Type 2 diabetes Mean age 60 y Mean DM duration 11.5 y Mean HbA1c 9.4% 40% had a CV event (n=1,791) Duckworth et al NEJM 2009;360:129-39
    • VADT Primary Time from Endpoint randomization to first occurrence of major CV event* * Composite of myocardial infarction, stroke, death from CV causes, CHF, surgery for vascular disease, inoperable coronary disease and amputation for ischemic gangrene Duckworth et al NEJM 2009;360:129-39
    • 1.0 VADT Results n = 235 0.8 Intensive therapy 0.6 Standard therapy n = 264 0.4 Intensive group median HbA1c 0.2 HR 0.88 (95%CI 0.74-1.05) Standard 8.4% P=0.14 Intensive 6.9% 0.0 0 2 4 6 8 Standard therapy 899 770 693 637 570 471 240 55 0 Intensive therapy 892 774 707 639 582 510 252 62 0 Duckworth et al NEJM 2009;360:129-39
    • Who will benefit No benefit from tight in VADT? glycemic control? Suggests that tight glycemic control appears to be ineffective at later stages Animal model of atherosclerosis Glucose plays an important role in lesion initiation Lipids play a more dominant role in lesion progression
    • Who will benefit UKPDS from tight Follow-up glycemic control? Objectives To determine whether the effects of improved glucose control on microvascular disease persisted 10 years after study completion UKPDS participants (n=3277) Whether such therapy had a Annual visits x 5 years long-term effect on Questionnaire x 5 more macrovascular outcomes years assessing outcomes Holman et al, NEJM 2008;359: 1577-89
    • UKPDS Follow-up Clinical Outcomes Any Diabetes- Myocardial diabetes- related death Death from Sudden death or death infarction related from MI, stroke, PVD, any cause Fatal or renal disease, hyper- or nonfatal MI endpoint * hypoglycemia Microvascular Glycemic Stroke PVD disease control at MD’s Amputation of at Vitreous discretion Fatal or least 1 digit or hemorrhage, retinal nonfatal stroke death from PVD Median ff-up photocoagulation or renal failure 17 y (range 16-30 y) * Sudden death, death from hyperglycemia or hypoglycemia, fatal or nonfatal MI, angina, heart failure, amputation, vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction Holman et al, NEJM 2008;359: 1577-89
    • Post-trial risk 1.4 P=0.052 reduction 15% P=0.01 1.2 1.0 0.8 0.6 0.4 Conventional therapy 186 212 239 271 296 319 Sulfonylurea–insulin 387 450 513 573 636 678 Holman et al, NEJM 2008;359: 1577-89
    • 1.0 Legacy Effect P=0.01 0.8 0.6 Conventional 0.4 therapy 0.2 Sulfonylurea–insulin 0.0 0 5 10 15 20 25 Conventional therapy 1138 1013 857 578 221 20 Sulfonylurea–insulin 2729 2488 2097 1459 577 66 Holman et al, NEJM 2008;359: 1577-89
    • Who will benefit Meta-analysis from tight glycemic control? Objective To summarize clinical benefits and harms of intensive vs conventional glucose control for adults n = 27,802 with type 2 diabetes UKPDS 33, 1998 UKPDS 34, 1998 ACCORD, 2008 ADVANCE, 2008 VADT, 2009 Kelly et al, Ann Intern Med Jul 2009;151: 394-403
    • Fatal stroke 39/11 591 52/11 591 0.75 (0.49 to 1.14) –1 (–3 to 1) PAD 374/6463 406/6468 0.92 (0.81 to 1.06) –5 (–9 to –1) Intensive glucose control reduced 0.5 1.0 2.0 the risk for nonfatal MI Relative Risk (95% CI) C. All Trials Event Events/Total, n/n Relative Risk Risk Difference (95% CI) (95% CI) Intensive Conventional Nonfatal MI 611/14 662 598/13 140 0.84 (0.75 to 0.94) –9 (–16 to 3) Fatal MI 540/14 662 437/13 140 0.94 (0.75 to 1.18) –3 (–10 to 4) Nonfatal stroke 423/14 662 362/13 140 0.98 (0.82 to 1.17) –3 (–7 to 2) Fatal stroke 88/14 662 76/13 140 0.87 (0.63 to 1.20) 0 (–2 to 1) PAD 409/9534 433/8017 0.91 (0.79 to 1.03) –3 (–5 to –1) 0.5 1.0 2.0 Relative Risk (95% CI) infarction; PAD peripheral artery disease. Intensive glucose control did not reduce the risk for CV death or all-cause mortality and increased the risk for 15 September 2009 Annals of Internal Medicine Volume 1 severe hypoglycemia Kelly et al, Ann Intern Med Jul 2009;151: 394-403
    • ↓ 0.9% HbA1c over 5 years from baseline 7.8% NNT 87 ↓ 1 mmol/L ↓ 4 mm Hg Benefit from glycemic LDL prevents BP prevents 8.2 CV events 12.5 CV control is modest events compared to control of lipids and blood pressure Ray et al, Lancet 2009;373:1765-72
    • Who will benefit Summary from tight glycemic control? Glycemic control does play a role in reducing CV complications ... Start early in the disease course Individuals in the ACCORD, ADVANCE and VADT have had diabetes 8 to 11 years at start of trial Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72
    • Who will benefit Summary from tight glycemic control? Glycemic control does play a role in reducing CV complications ... Benefit becomes evident only after a long period of time Follow-up periods in the ACCORD, ADVANCE and VADT were between 3.5 to 5 years Follow-up time required to demonstrate macrovascular benefit in UKPDS was median of 17.8 years Cheng & Leiter, Current Diabetes Reports 2009;9: 65-72
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Primary Prevention of CVD in People with Diabetes Mellitus A Scientific Statement from AHA & ADA A1c goal for patients in general is <7% A1c goal for the individual patients is an A1c as close to What should be normal (<6%) as possible the target HbA1c? without causing hypoglycemia Buse, Circulation 2007;115:114-26
    • HbA1c <7% OR <6.5%? Not enough basis for <7% Kumamoto study is the only long-term study with clinical events as primary outcomes HbA1c data from UKPDS, What should be ACCORD, ADVANCE and VADT the target HbA1c? considered observational Participants randomized to A1c target not to the level achieved Lund & Vaag, Diabetes Care Jul 2009;32(7):e90
    • HbA1c <7% OR <6.5%? Hypoglycemia increases What should be the target HbA1c? as HbA1c target decreases
    • HbA1c <7% OR <6.5%? A1c target <6.5% might not increase hypoglycemia per se ADVANCE intensive group had 2-3% higher hypoglycemia risk than conventional group Lower than hypoglycemia risk in What should be ACCORD/VADT intensive group the target HbA1c? (~15-20%) Lower than hypoglycemia risk in ACCORD/VADT conventional group (~5-10%) Lund & Vaag, Diabetes Care Jul 2009;32(7):e90
    • Mortality Analyses in Hypoglycemia not significantly related to excess mortality in ACCORD intensive group Intensive control increased mortality irrespective of pre- existing CVD In patients with preexisting CVD, What should be intensive control had no effect on the target HbA1c? CVD (i.e. no harm) Hypoglycemia did not explain the increased mortality Lund & Vaag, Diabetes Care Jul 2009;32(7):e90
    • Mortality Analyses in ACCORD In both arms, patients with severe hypoglycemia had higher mortality than those without Higher mortality in standard arm among participants with at least one episode of severe What should be hypoglycemia the target HbA1c? Higher mortality in intensive arm among participants with no history of severe hypoglycemia Skyler et al, J Am Coll Cardiol 2009;53:298-304
    • Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA Lower A1c goal if can be achieved without significant hypoglycemia Short duration of diabetes Long life expectancy No significant CVD What should be the target HbA1c? General A1c goal <7% Skyler et al, J Am Coll Cardiol 2009;53:298-304
    • Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE and VA Diabetes Trials A Position Statement of the ADA and a Scientific Statement of the ACC & AHA Less stringent A1c goal History of severe hypoglycemia Limited life expectancy Advanced micro- or macrovascular complications or extensive comorbid conditions Long-standing diabetes which is difficult to control What should be the target HbA1c? General A1c goal <7% Skyler et al, J Am Coll Cardiol 2009;53:298-304
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
    • UKPDS Overweight patients on Metformin ↓ MI by 39% (p=0.01) ↓ all-cause mortality by 36% (p=0.01) How do current therapies for diabetes compare? Holman et al, NEJM 2008;359: 1577-89
    • Legacy Effect 1.0 P=0.005 0.8 0.6 Conventional therapy 0.4 0.2 Metformin 0.0 0 5 10 15 20 25 Conventional therapy 411 360 311 213 95 4 Metformin 342 317 274 214 106 16 Holman et al, NEJM 2008;359: 1577-89
    • 1.0 Legacy Effect P=0.01 0.8 0.6 Conventional 0.4 therapy 0.2 Sulfonylurea–insulin 0.0 0 5 10 15 20 25 Conventional therapy 1138 1013 857 578 221 20 Sulfonylurea–insulin 2729 2488 2097 1459 577 66 Holman et al, NEJM 2008;359: 1577-89
    • PROACTIVE PROspective PioglitAzone Clinical Trial In macroVascular Events How do current therapies for Objective diabetes compare? To determine if treatment with pioglitazone will decrease CV events in high- risk patients with type 2 diabetes Type 2 diabetes Evidence of CVD Continued on current treatment Randomized to pioglitazone or placebo Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40
    • PROACTIVE Endpoints Composite of all-cause mortality, non-fatal MI, stroke, ACS, endovascular/surgical intervention in coronary/leg arteries or amputation above the ankle Secondary endpoint: composite of all- cause mortality, non-fatal MI and stroke Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40
    • PROACTIVE Primary Endpoint Dormandy et al, Lancet 2005;366:1279-89
    • PROACTIVE Secondary Endpoint
    • How do current Pioglitazone therapies for PROACTIVE diabetes compare? Unclear whether the effect of pioglitazone on macrovascular endpoints is a unique property of the drug Slight improvements in SBP, TG and HDL-C unlikely to get individual patients to goal 40% higher risk of CHF unsurprising Singaram & Pratley, Diabetes Vasc Dis Res 2007; 4:237-40
    • Meta-analysis How do current therapies for diabetes compare? Objective To systematically examine the peer-reviewed literature on the CV risk associated with oral agents 40 controlled trials that reported CV events (primarily MI and stroke) Selvin et al, Arch Intern Med 2008;168(19):2070-80
    • Meta-analysis How do current therapies for diabetes compare? Results Metformin ↓ risk of CV mortality (OR 0.74; 95%CI 0.62-0.89) Rosiglitazone ↑ risk of CV morbidity or mortality but not statistically significant (OR 1.68; 95%CI 0.92-3.06) No other significant associations for other oral agents 40 controlled trials that reported CV events (primarily MI and stroke) Selvin et al, Arch Intern Med 2008;168(19):2070-80
    • How do current therapies for diabetes BARI 2D compare? Prompt coronary Medical Therapy revascularization Insulin sensitization Insulin sensitization therapy therapy (Metformin/RSG) (Metformin/RSG) Prompt coronary Medical Therapy revascularization Insulin provision Insulin provision therapy therapy (SU/Insulin) (SU/Insulin) Type 2 diabetes and heart disease (n=2,368) Randomization stratified according to choice of PCI or CABG BARI 2D Study Group, NEJM 2009;360:2503-15
    • BARI 2D Endpoints Death rate Composite of death, MI or stroke BARI 2D Study Group, NEJM 2009;360:2503-15
    • 100 Insulin sensitization 90 88.2 80 87.9 Insulin provision 70 60 50 40 P=0.89 30 20 10 0 0 1 2 3 4 5 2368 2296 2247 2197 1892 1196 BARI 2D Study Group, NEJM 2009;360:2503-15
    • 100 90 Insulin sensitization 80 77.7 70 75.4 Insulin provision 60 P=0.13 50 40 30 Insulin sensitization strategy 20 Fewer severe hypoglycemia, less 10 weight gain and higher HDL-C 0 0 1 2 3 4 5 2368 2094 1984 1807 1459 823 BARI 2D Study Group, NEJM 2009;360:2503-15
    • Who will benefit from tight glycemic control? Cardiovascular Disease Prevention
    • Who will benefit from tight glycemic control? What should be the target HbA1c? Cardiovascular Disease Prevention
    • Who will benefit How do current from tight therapies for glycemic control? diabetes compare? What should be the target HbA1c? Cardiovascular Disease Prevention
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