Διαβητική)μακροαγγειοπάθεια).) Υπάρχει)πρόληψη;) Δ.Σκούτας) Ειδικός)παθολόγος>Διαβητολόγος) Διδάκτωρ))Ιατρικής)Σχολής)ΔΠΘ)

Διαβητική)μακροαγγειοπάθεια).) Υπάρχει)πρόληψη;) Δ.Σκούτας) Ειδικός)παθολόγος>Διαβητολόγος) Διδάκτωρ))Ιατρικής)Σχολής)ΔΠΘ)

Major)microvascular)and)macrovascular) complicarons)of)diabetes) Microvascular 1,2 Macrovascular 1,2 Cognitive impairment 3 Diabetic retinopathy Diabetic nephropathy Cerebrovascular disease Coronary disease Coronary heart disease Diabetic neuropathy Cardiac autonomic neuropathy Atherosclerosis Skin infection Gastro-intestinal and bladder dysfunction Peripheral vascular disease Sexual dysfunction Peripheral sensory dysfunction Diabetic foot Adapted from: 1. International Diabetes Foundation. Time to Act: Type 2 diabetes, the metabolic syndrome and cardiovascular disease in Europe. 2006. 2. International Diabetes Federation. Time to Act. 2001. 3. Seaguist ER. Diabetes. 2010;59:4-6.

Hospital)costs)for)paRents)with)and)without) diaberc)complicarons) Hospital costs (2008 Int$) 5000 4000 3000 2000 1000 Asia Eastern Europe Established Market Economies 0 No complications* Major coronary Major cerebrovascular Heart failure Peripheral vascular Nephropathy Diabetes complication in same year * No complications signifies none of the 5 complications listed Clarke PM, et al. PLoS Med. 2010 23;7(2):e1000236.

Type)2)diabetes)significantly)increases)the)risk) of)cardiovascular)disease) Overall, people with diabetes are 2-4 times more likely to develop cardiovascular disease than those without diabetes 1 The cardiovascular triad 1 Cerebrovascular disease 2 4 times increased risk of stroke 2,3 2-6-times greater risk of TIA 1 Coronary heart disease 2-times increased risk of CHD 3,4 2-times increased risk of non-fatal MI 3 2-3-times increased risk of heart failure 1 Peripheral vascular disease Alongside microvascular disease and neuropathy, contributes to: 1 15-40-times higher risk of lower-limb amputation 3-9-times higher risk of intermittent claudication 1. International Diabetes Federation. Time to Act. 2001. Available at: http://www.idf.org/webdata/docs/diabetes%20and%20cvd.pdf. Accessed: September 5, 2010. 2. Folsom AR, et al. Diabetes Care. 1999;22:1077-83. 3. Emerging Risk Factors Collaboration. Lancet. 2010;375:2215-22. 4. Huxley R, et al. BMJ. 2006;332:73-8.

Diabetes)significantly)increases)the)risk)of)vascular) outcomes:)meta>analysis)of)102)prospecrve)studies) Hazard ratios* for vascular outcomes in people with vs without diabetes at baseline (n=530,083) Number of cases HR (95% CI) l 2 (95% CI) Coronary heart disease* 26,505 2.00 (1.83-2.19) 64 (54-71) Coronary death 11,556 2.31 (2.05-2.60) 41 (24-54) Non-fatal myocardial infarction 14,741 1.82 (1.64-2.03) 37 (19-51) Stroke subtypes Ischaemic stroke 3799 2.27 (1.95-2.65) 1 (0-20) Haemorrhagic stroke 1183 1.56 (1.19-2.05) 0 (0-26) Unclassified stroke 4973 1.84 (1.59-2.13) 33 (12-48) Other vascular deaths 3826 1.73 (1.51-1.98) 0 (0-26) 1 2 4 *Adjusted for age, smoking status, body mass index, systolic blood pressure, and where appropriate stratified by sex and trial arm Includes both fatal and non-fatal events Emerging Risk Factors Collaboration. Lancet. 2010;375:2215-22.

Incidence)of)cardiovascular)events)in)people) with)type)2)diabetes:)darts)registry) Incidence rate per 1000 patients 50 40 30 20 10 0 38.4 Angina 21.9 Myocardial infarction 14.2 Cerebrovascular accident 13.6 Peripheral vascular disease McAlpine RR, et al. Diabetes Med. 2005;22:348-52.

Long>term)cardiovascular)and)non>cardiovascular) mortality)in)parents)with)type)2)diabetes) Standardised mortality rates (SMR) for men and women with type 2 diabetes All-cause mortality Patientyears* 0 2 4 6 8 10 Increased risk of mortality SMR (95% CI) Women 2625 4.7 (3.9-5.8)** Men 3183 3.0 (2.5-3.5) All 5807 3.5 (3.1-4.0) Cardiovascular mortality Women 2591 7.2 (5.3-9.8)** Men 3139 4.4 (3.4-5.6) All 5730 5.2 (4.3-6.3) Non-cardiovascular mortality Women 2591 3.1 (2.3-4.2) Men 3139 2.1 (1.6-2.7) All 5730 2.4 (2.0-3.0) *Follow-up from 1974-2005 for all-cause mortality and 1974-2004 for cardiovascular and non-cardiovascular mortality **p<0.01 for difference between men and women Allemann S, et al. Swiss Med Wkly. 2009;139(39-40):576-83.

Type)2)diabetes)increases)cardiovascular)risk)) as)much)as)a)previous)history)of)mi) 7-year incidence of cardiovascular events among patients with type 2 diabetes vs no diabetes stratified by history of MI Incidence of CV events (%) 50 40 30 20 10 0 p <0.001 No history of MI History of MI 45.0 p <0.001 20.2 18.8 3.5 n = 890 n = 169 n = 1304 n = 69 Type 2 diabetes Non-diabetic Haffner SM, et al. N Engl J Med. 1998;339:229-34.

Hyperglycaemia)and)diabetes)complicaRons:) underlying)mechanisms) Hyperglycaemia Biochemical changes 1-3 Accumulation of sorbitol and fructose Glycation of proteins Activation of protein kinase C Increased oxidative stress Increased coaguability Increased vascular permeability Tissue damage 1-4 Atherogenesis Changes in renal glomerular function Neuronal damage Retinal damage due to microvascular changes and neuropathy Microvascular and macrovascular complications 1. Gerich JE. Arch Intern Med. 2003;163:1306-16. 2. Blézquez-Medela AM, et al. Curr Diabetes Rev. 2010;6(2):68-87. 3. Brownlee M. Diabetes. 2005;54:1615-25. 4. Oshitari T, et al. VHRM. 2008:4(1) 115 22.

Υπεργλυκαιμία)και)αθηρογένεση)

Διαβητική)δυσλιπιδαιμία)και)αγγειακό)τοίχωμα)

Φλεγμονή)σακχαρώδης)διαβήτης)τύπου)2)και) αθηρωμάτωση)

Micro>)and)macrovascular)complicaRons)increase) as)a)funcron)of)hba 1c )in)type)2)diabetes:)ukpds ) Adjusted incidence per 1000 person years (%) 60 50 40 30 20 10 0 5.5 6.5 7.5 8.5 Microvascular endpoints 9.5 Updated mean HbA 1c concentration (%) Myocardial infarction 10.5 Estimated 37% decrease in microvascular risk for each 1% reduction in HbA 1c (p<0.0001) Estimated 14% decrease in myocardial infarction risk for each 1% reduction in HbA 1c (p<0.0001) Stratton IM, et al. BMJ. 2000;321:405-12.

Intensive)glycaemic)control:)incremental)risk) reducron)with)decreasing)hba 1c )in)ukpds) Risk)reducRons)for)every)1%)reducRon)in)HbA 1c )) Relative Risk* 95% CI Microvascular complications 37% 33-41 Any diabetes-related endpoint 21% 17-24 Diabetes-related death 21% 15-27 All-cause mortality 14% 9-19 Fatal and non-fatal MI 14% 8-21 *All p<0.0001 Newly diagnosed type 2 diabetes at baseline; 7.5-12.5 years follow-up (median = 10.0 years) Stratton IM, et al. BMJ. 2000;321:405-12.

Long>term)intensive)glycaemic)control:)reduced)risk) of)mi)in)ukpds)post>trial)monitoring) Results after a median of 8.5 years post-trial follow-up 1 Aggregate endpoint 1997 2 2007 1 Any diabetes-related endpoint RRR: P: 12% 0.029 9% 0.04 Microvascular disease RRR: P: 25% 0.0099 24% 0.001 Myocardial infarction RRR: P: 16% 0.052 15% 0.01 All-cause mortality RRR: P: 6% 0.44 13% 0.007 RRR: Relative Risk Reduction with intensive glycaemia control (sulphonylurea-insulin) vs conventional therapy; P: Log Rank Median diabetes duration at baseline = 10.0 years + 8.5 years follow up 1. Holman R. N Engl J Med. 2008;359:1577-89. 2. UKPDS 33. Lancet. 1998;352:837-53.

Intensive)glycaemic)control:)reduced)long>term)risk)of) macrovascular)complicarons)in)type)1)diabetes)parents)in) DCCT>EDIC) Any CV outcome Non-fatal MI, stroke, or death from CVD Cumulative incidence Intensive Conventional 0.12 42% risk reduction p=0.02 0.10 0.08 0.06 0.04 0.02 0.00 0 2 4 6 8 10 12 14 16 18 20 Intensive Conventional 0.12 0.10 0.08 0.06 57% risk reduction )p=0.02 0.04 0.02 0.00 0 2 4 6 8 10 12 14 16 18 20 Years since entry Years since entry No. at Risk Conventional Intensive 714 705 688 683 618 629 92 113 721 705 694 686 637 640 96 118 CV: cardiovascular; MI: myocardial infarction; CVD: cardiovascular disease DCCT-EDIC Study Research Group. N Engl J Med. 2005;353:2643-53.

Recent)trial)outcomes)for)intensive)glycaemic)control)in)paRents) with)advanced)type)2)diabetes:)advance,)accord,)vadt) Summary of study key features and results 1 ADVANCE (11,140) 2 ACCORD (10,251) 3 VADT (1791) 4 Achieved HbA 1c (%) (STD vs INT) 7.3 vs 6.5 7.5 vs 6.4 8.4 vs 6.9 Primary outcome Non-fatal MI, non-fatal stroke, CVD death Non-fatal MI, non-fatal stroke, CVD death MI, stroke, death from CV causes, new or worsening CHF, revascularisation and inoperable CAD, amputation for ischaemic gangrene HR* (95% CI) for primary outcome HR* (95% CI) for mortality 0.94 (0.84-1.06) 0.90 (0.78-1.04) 0.87 (0.730-1.04) 0.93 (0.83-1.06) 1.22 (1.01-1.46) a 1.065 (0.801-1.416) HR* (95% CI) for microvascular outcomes 0.86 (0.77-0.97) b Primary composite, 0.95 (0.85-1.07) 5 Significant improvements in 7 secondary measures c No significant differences in individual microvascular outcomes * INT vs STD; a p=0.04; b p=0.01; c p<0.05 for incident microalbuminuria, incident macroalbuminuria, cataract surgery, 3-line worsened visual acuity, neuropathy (MNSI score >2.0), loss of ankle jerk, loss of sensation to light touch STD, standard therapy; INT, intensive therapy; CAD: coronary artery disease; CHF: congestive heart failure; CVD: cardiovascular disease; MI: myocardial infarction 1. Del Prato S. Diabetologia. 2009;52:1219-26. 2. ADVANCE Study Group. N Engl J Med. 2008;358:2560-72. 3. ACCORD. New Engl J Med. 2008;358:2545-59. 4. Duckworth W, et al. N Engl J Med. 2009;360:129-39. 5. Ismail-Beigi F, et al. Lancet. 2010;376(9739):419-30.

Intensive)glycaemic)control:)reduced)microvascular) but)not)macrovascular)events)in)advance) Major macrovascular events Major microvascular events Intensive Standard Intensive Standard Cumulative incidence (%) 25 20 15 10 5 0 )p=0.32 HR for intensive vs standard 0.94 (95% CI, 0.84 to 1.06)" 0 6 12 18 24 30 36 42 48 54 60 66 25 20 15 10 5 0 )p=0.01 HR for intensive vs standard 0.86 (95% CI, 0.77 to 0.97)" 0 6 12 18 24 30 36 42 48 54 60 66 Months of follow-up Months of follow-up No. at Risk Intensive Standard 5570 5494 5428 5569 5486 5413 5338 5256 5176 5330 5237 5163 5097 5005 4927 5084 4995 4922 4396 2071 4385 2108 486 509 5571 5495 5430 5569 5498 5431 5358 5233 5120 5353 5207 5069 5055 4968 4824 4995 4911 4764 4258 1992 4204 2024 473 494 ADVANCE Study Group. N Engl J Med. 2008;358:2560-72.

Intensive)glycaemic)control:)decreased)non>fatal)MI) but)increased)all>cause)and)cv)mortality)in)accord) Hazard&ra'o&for&outcomes&with&intensive&vs&standard&therapy& Outcome % with outcome INT (n=5128) STD (n=5123) Hazard ratio (95% CI) Primary outcome 6.9 7.2 0.90 (0.78-1.04) Secondary outcomes Death Any cause 5.0 4.0 1.22 (1.01-1.46)* CV causes 2.6 1.8 1.35 (1.04-1.76)* Non-fatal MI 3.6 4.6 0.76 (0.62-0.92)** Non-fatal stroke 1.3 1.2 1.06 (0.75-1.50) Fatal/non-fatal CHF 3.0 2.4 1.18 (0.93-1.49) *p<0.05; **p<0.01 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Composite of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes Increased risk of outcome CV: Cardiovascular; INT: Intensive therapy; STD: Standard therapy. with INT vs STD ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

Intensive)glycaemic)control:)risk)of)primary)outcome)in) pre>specified)subgroups)in)accord) Better outcomes were observed with intensive treatment in subjects with no previous history of CV disease Median diabetes duration at baseline = 10 years Subgroup No. of subjects No. of events Hazard ratio P value Total Previous cardiovascular event No Yes Sex Female Male Age at baseline <65 yr 65 yr Glycated haemoglobin at baseline 8.0% >8.0% Race Non-white White 10,251 6643 3608 3952 6299 6779 3472 4868 5360 3647 6604 723 330 393 212 511 383 340 284 438 222 501 0.04 0.74 0.65 0.03 0.29 0.6 1.0 1.4 Intensive therapy better Standard therapy better ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

Intensive)glycaemic)control:)significantly)greater)risk)of) hypoglycaemia)in)accord) Proportion of participants with hypoglycaemia Annualised rate of hypoglycaemic episodes requiring medical assistance was 3.1% in the intensive-therapy and 1.0% in the standard-therapy group 20 * 16.2 Intensive therapy Percentage (%) 15 10 5 5.1 * 10.5 3.5 Standard therapy *P<0.001 vs Standard therapy 0 Requiring any assistance Requiring medical assistance Median diabetes duration at baseline = 10 years ACCORD Study Group. N Engl J Med. 2008;358:2545-9.

Intensive)glycaemic)control:)impact)of)duraRon)of) diabetes)on)risk)of)cvd)in)vadt) Duration of type 2 diabetes and risk of CVD with intensive therapy Hazard ratios for CVD owing to IGC was found to increase with the duration of diabetes 1,2 1.4 1.2 HR for CVD 1 0.8 0.6 0.4 0 3 6 9 12 15 18 21 24 Diabetes duration, years P<0.0001 Mean diabetes duration at baseline = 11.5 years CVD: Cardiovascular disease; IGC: Intensive glucose control 1. Del Prato S. Diabetologia. 2009;52:1219-2. 2. Duckworth W. ADA Scientific Sessions 2008. Available at: http://webcasts.prous.com/netadmin/webcast_viewer/preview.aspx?type=0&lid=3853. Accessed: 5 Oct, 2009.

Bad)glycaemic)legacy:)hypotheRcal)Rme)course)of)glycaemia) before)and)a{er)intensive)treatment)in)vadt) Hypothetical representation of the natural history of diabetes patients recruited in VADT HbA 1c (%) 9.5 9.0 8.5 8.0 7.5 7.0 Before entering VADT intensive treatment arm Generation of a bad glycaemic legacy After entering VADT intensive treatment arm Drives risk of complications Upper dotted line represents the time course of HbA 1c estimated on the basis of the average glucose profile described by the UKPDS Lower dotted line represents the ideal time course of glycaemic control. The solid line represents the time course of HbA 1c in the VADT 6.5 6.0 Mean diabetes duration at baseline = 11.5 years 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time since diagnosis (years) Del Prato S. Diabetologia. 2009;52:1219-26.

Hypoglycaemia)was)a)major)predictor) of)cardiovascular)death)in)the)vadt)study) Hypoglycaemia Hazard Ratio (confidence limits) 4.042 (1.449, 11.276) P Value 0.01 HbA 1c 1.213 (1.038, 1.417) 0.02 HDL 0.699 (0.536, 0.910) 0.01 Age 2.090 (1.518, 2.877) <0.01 Prior event 3.116 (1.744, 5.567) <0.01 0 2 4 6 8 10 12 Hazard ratio (confidence limits) Duckworth W. Presented at the ADA 68th Scientific Sessions, 2008. Available at: http:// professional.diabetes.org/presentations_details.aspx?session=3167.

Meta>analyses)of)RCTs)on)macrovascular)outcomes) with)intensive)glycaemic)control:)study)designs) Inclusion criteria (pre-defined) Studies included Studies excluded Ray, et al. 2009 1 Turnbull, et al. 2009 2 Random assignment of T2D intensive vs standard care CV outcomes, MI, stroke, mortality Stable patients ACCORD ADVANCE PROactive UKPDS VADT RECORD, ADOPT no CV outcomes DREAM, UGDP patients with IGT STENO-2 not vs standard care Randomised, controlled trials designed to assess low vs high glycaemia on CV risk CV outcomes >1000 person-years follow-up ACCORD ADVANCE UKPDS VADT No. of patients 33,040 patients 27,049 patients All others in part due to collaboration of the investigators of the 4 trials included RCT: randomised, controlled trial; MaV: macrovascular 1. Ray KK, et al. Lancet. 2009;373:1765-72. 2. Turnbull FM, et al. Diabetologia. 2009;52:2288-98.

Meta>analysis)of)RCTs)shows)significant)macrovascular)risk) reducron)with)intensive)glycaemic)control:)non>fatal)mi) Effect&of&IGC&on&non<fatal&MI:&<17%&for&<0.9%&HbA1c&&&&&&&&&&&&&&&&&(~33,040)paRents;)~163,000) person>years)of)follow>up)) Intensive treatment/standard treatment Participants Events Weight of study size Odds ratio (95% CI) Odds ratio (95% CI) UKPDS 3071/1549 221/141 21.8% 0.78 (0.62-0.98) PROactive 2605/2633 119/144 18.0% 0.83 (0.64-1.06) ADVANCE 5571/5569 153/156 21.9% 0.98 (0.78-1.23) VADT 892/899 64/78 9.4% 0.81 (0.58-1.15) ACCORD 5128/5123 186/235 28.9% 0.78 (0.64-0.95) Overall 17267/15773 743/754 100% 0.83 (0.75-0.93) 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Intensive treatment better Standard treatment better RCT: randomised, controlled trial; MaV: macrovascular event; IGC: intensive glucose control; MI: myocardial infarction Ray KK, et al. Lancet. 2009;373:1765-72.

Meta>analysis)of)RCTs)shows)significant)macrovascular)risk) reducron)with)intensive)glycaemic)control:)chd)events) Effect&of&IGC&on&CHD&events:&<15%&for&<0.9%&HbA1c)) (~33,040)paRents;)~163,000)person>years)of)follow>up)) Intensive treatment/standard treatment Participants Events Weight of study size Odds ratio (95% CI) Odds ratio (95% CI) UKPDS 3071/1549 426/259 8.6% 0.75 (0.54-1.04) PROactive 2605/2633 164/202 20.2% 0.81 (0.65-1.00) ADVANCE 5571/5569 310/337 36.5% 0.92 (0.78-1.07) VADT 892/899 77/90 9.0% 0.85 (0.62-1.17) ACCORD 5128/5123 205/248 25.7% 0.82 (0.68-0.99) Overall 17267/15773 1182/1136 100% 0.85 (0.77-0.93) 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 Intensive treatment better Standard treatment better RCT: randomised, controlled trial; MaV: macrovascular event; IGC: intensive glucose control; CHD: coronary heart disease Ray KK, et al. Lancet. 2009;373:1765-72.

Meta>analysis)of)RCTs)shows)significant)macrovascular)risk) reducron)with)intensive)glycaemic)control:)fatal)and)non>fatal MI) Effect&of&IGC&on&fatal&and&non<fatal&MI:&<15%&for&<0.88%&HbA1c)) (~27,000)paRents)) Number of events (annual event rate, %) Trials More intensive Less intensive HbA 1c (%) Favours more intensive Favours less intensive Hazard ratio (95% CI) Myocardial infarction ACCORD 198 (1.18) 245 (1.51) -1.01 0.77 (0.64-0.93) ADVANCE 310 (1.18) 337 (1.28) -0.72 0.92 (0.79-1.07) UKPDS 150 (1.20) 76 (1.40) -0.66 0.81 (0.62-1.07) VADT 72 (1.65) 87 (1.99) -1.16 0.83 (0.61-1.13) Overall 730 745-0.88 0.85 (0.76-0.94) Q=2.25, p=0.52, l 2 =0.0% 0.5 1.0 2.0 Hazard ratio (95% CI) RCT: randomised, controlled trial; MaV: macrovascular event; IGC: intensive glucose control; MI: myocardial infarction Turnbull FM, et al. Diabetologia. 2009;52:2288-98.

Meta>analysis)of)RCTs)shows)significant)macrovascular)risk) reducron)with)intensive)glycaemic)control:)major)cv)events) Effect&of&IGC&on&major&CV&events*:&<9%&for&<0.88%&HbA1c&& (~27,000)paRents)) Number of events (annual event rate, %) Trials More intensive Less intensive HbA 1c (%) Favours more intensive Favours less intensive Hazard ratio (95% CI) Major CV events ACCORD 352 (2.11) 371 (2.29) -1.01 0.90 (0.78-1.04) ADVANCE 557 (2.15) 590 (2.28) -0.72 0.94 (0.84-1.06) UKPDS 169 (1.30) 87 (1.60) -0.66 0.80 (0.62-1.04) VADT 116 (2.68) 128 (2.98) -1.16 0.90 (0.70-1.16) Overall 1,194 1,176-0.88 0.91 (0.84-0.99) Q=1.32, p=0.72, l 2 =0.0% 0.5 1.0 2.0 Hazard ratio (95% CI) RCT: randomised, controlled trial; MaV: macrovascular event; IGC: intensive glucose control; CV: cardiovascular * Non-fatal stroke, non-fatal MI or CV death Turnbull FM, et al. Diabetologia. 2009;52:2288-98.

Meta>analyses)on)the)effect)of)intensive)glucose)control)on) macrovascular)outcomes)in)type)2)diabetes) Consistent cardiovascular (CV) benefit with intensive vs standard glucose lowering over ~5 years of follow-up (achieved HbA 1c reduction = 0.9%) in type 2 diabetes patients was shown 1,2 Participants Ray et al 1 33,040 Events (intensive/ standard therapy) Odds ratio (95% CI) Non-fatal MI 743/754 0.83 (0.75-0.93) CHD events 1182/1136 0.85 (0.77-0.93) All-cause mortality 1573/1319 1.02 (0.87-1.19) Turnbull et al 2 27,049 Fatal/non-fatal MI 730/745 0.85 (0.76-0.94) Major CV events* 1194/1176 0.91 (0.84-0.99) All-cause mortality 980/884 1.04 (0.90-1.20) * Non-fatal stroke, non-fatal MI or CV death Decreased risk of mortality with intensive vs standard treatment 0.6 0.8 1.0 1.2 1. Ray KK, et al. Lancet. 2009;373:1765-72. 2. Turnbull FM, et al. Diabetologia. 2009;52:2288-98

Meta>analyses)of)RCTs)on)macrovascular)outcomes)with) intensive)glycaemic)control:)summary)and)recommendarons) Both meta-analyses show consistent CV benefit with intensive glucose lowering 1,2 : HbA 1c reduction with ~5 years of follow-up was 0.9% 15-17% risk reduction (RR) for MI 9% and 15% RR for CV and CHD events, respectively No increased risk of stroke or all-cause mortality Practical clinical implications Initiate therapy early, before any microor macrovascular disease Reduce HbA 1c steadily with care to avoid hypoglycaemia A combination of glucose-lowering agents may be needed to achieve lower glycaemic targets 1. Ray KK, et al. Lancet. 2009;373:1765-72. 2. Turnbull FM, et al. Diabetologia. 2009;52:2288-98.

A1C)as)a)Predictor)of)CHD)in)Type)2) Diabetes) * p <0.01 vs lowest tertile p <0.05 vs lowest tertile Kuuisto J et al, Diabetes 43:960-967 (1994).

CV)events)as)a)funcRon)of)HbA 1c )in)people)with)type)2) diabetes:)retrospecrve)cohort)study) Impact)of)treatment)intensificaRon)on)outcomes)in)type)2)diabetes)paRents) (aged) 50)years))in)a)primary>care)seÜng)(UK)General)PracRce)Research)Database)) Low&and&high&HbA 1c &were&associated&with&increased&incidence&of&cv&events& Progression to first large-vessel disease event by HbA 1c decile in people with no previous CVD HR (95% CI) 1.9 1.7 1.5 1.3 * Hazard ratio vs 4th HbA 1c decile (median 7.5%): Decile 1 (lowest): 1.54 (1.28-1.84) Decile 10 (highest): 1.36 (1.14-1.61) * 1.1 0.9 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 HbA 1c (%) Adjusted for age, sex, Charlson index (age unadjusted), total cholesterol, smoking status history and cohort membership *Truncated at lower quartile; Truncated at upper quartile Currie CJ, et al. Lancet. 2010;375:481-9.

Survival)as)a)funcRon)of)HbA 1c )in)type)2)diabetes:) All>cause)mortality) Low and high HbA 1c values were associated with increased mortality and CV events For oral therapies significant only for the lowest (median 6.4%) and highest (median 10.6%) HbA 1c deciles For insulin-based regimens significant for HbA 1c deciles 1-3 (median 7.3%) and 9-10 (median 9.4%) HR (95% CI) 2.4 2.2 2.0 1.8 1.6 1.4 1.2 * * *) Adjusted HR for all-cause mortality by HbA 1c deciles * *) * *) * * *) * *) * *) * *) 1.0 0.8 0.6 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 HbA 1c (%) HbA 1c (%) Metformin plus sulphonylureas (n=27,965) Insulin-based regimens (n=20,005) Adjusted for age, sex, smoking status, total cholesterol, cardiovascular risk and general morbidity *Truncated at lower quartile; Truncated at upper quartile **p<0.01 vs the reference group (decile 4; median HbA 1c 7.5) Currie CJ, et al. Lancet 2010 ;375:481-9

Oral)glucose>lowering)agents:)effects)on)CV)risk)factors) Effects on CV risk factors Metformin 1 Sulphonylureas 1 Thiazolidinediones 2-4 DPP-4 inhibitors 5,6 Glinides 2 α-glucosidase inhibitors 1 Small decrease in LDL-cholesterol levels and triglycerides No adverse effect on blood pressure No weight gain, with possible modest weight loss Hypoglycaemia, weight gain No specific effect on plasma lipids or blood pressure Weight gain Increased risk of myocardial ischaemic events (rosiglitazone) and congestive heart failure (rosiglitazone, pioglitazone) No increase in risk of CV events in large metaanalysis of Phase 2b/3 studies Not associated with hypoglycaemia or weight gain Hypoglycaemia, weight gain Not associated with hypoglycaemia or weight gain On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone ) 1. Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411. 2. Nathan DM, et al. Diabetologia. 2009;52:17-30. 3. Avandia, Summary of Product Characteristics, EMEA, 6 Mar 2008. 4. Actos, Summary of Product Characteristics, EMEA, 6 Sep 2007. 5. Ahrèn B. Expert Opin Emerg Drugs. 2008;13:593-60. 6. Frederich R, et al. Postgrad Med. 2010;122(3):16-27.

ReducRon)(%))in)risk)with)meäormin)in)overweight)) Type)2)diabetes)paRents:)UKPDS) Diabetes-related endpoints Diabetes-related deaths All-cause mortality Myocardial infarction 0 5 Risk reduction (%) 10 15 20 25 30 35 40 45 32% p=0.002 42% p=0.017 36% p=0.011 39% p=0.010 n=342 P-values in comparison to conventional treatment group United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-65.

Risk)of)CVD)hospitalisaRons)and)CVD)mortality)with) sulphonylurea/meäormin)combinaron)therapy) Relative Risk (95% CI) No. of Events/Total Combination Therapy Control Group Bruno (1999) 1.04 (0.62, 1.75) Not specified Not specified Olsson (2000) 1.86 (1.33, 2.61) Not specified Not specified Johnson (2005) 0.96 (0.82, 1.12) 264/1081 541/2138 Koro (2005) 1.38 (1.13, 1.69) Not specified Not specified Evans (2006) 2.24 (1.26, 3.99) 133/1252 229/2286 Evans (2006) 1.86 (1.03, 3.35) 92/985 229/2286 Evans (2006) 1.52 (0.84, 2.76) 12/113 229/2286 Overall 1.43 (1.10, 1.85) 0.25 1.0 4.0 * Diet therapy, metformin monotherapy, or sulphonylurea monotherapy Rao AD, et al. Diabetes Care. 2008;31:1672-8.

RetrospecRve)cohort)study:)risk)of)congesRve)heart) failure)with)oral)glucose>lowering)drugs) Retrospective cohort study using the UK General Practice ResearchDatabase (1990-2005) of 91,521 people with diabetes 2.0 Congestive heart failure (CHF) Hazard ratio (95% Cl) (log scale) 1.5 1.0 0.5 Increased risk of CHF Decreased risk of CHF *Any therapy (monotherapy and combinations) Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone Tzoulaki I, et al. BMJ. 2009;339:b4731 doi:10.1136/bmj.b4731 (3 Dec 2009, e-pub ahead of print). On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone )

RetrospecRve)cohort)study:)risk)of)myocardial) infarcron)with)oral)glucose>lowering)drugs) Retrospective cohort study using the UK General Practice Research Database (1990-2005) of 91,521 people with diabetes 2.0 Myocardial infarction (MI) Hazard ratio (95% Cl) (log scale) 1.5 1.0 0.5 Increased risk of MI Decreased risk of MI *Any therapy (monotherapy and combinations) Other drugs and combinations of any oral antidiabetes drugs excluding rosiglitazone and pioglitazone Tzoulaki I, et al. BMJ. 2009;339:b4731 doi:10.1136/bmj.b4731 (3 Dec 2009, e-pub ahead of print). On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone )

RECORD:)Acute)myocardial)infarcRon)with)rosiglitazone) Time to acute MI* in patients with type 2 diabetes assigned to rosiglitazone vs control (n=4447) 7 6 Rosiglitazone (43 events) Control (37 events) Cumulative incidence of acute MI (%) 5 4 3 2 1 HR=1.16; p=ns 0 0 12 24 36 48 60 Months *Adjudicated events only. Included hospitalisations and deaths. Home PD, et al. N Engl J Med. 2007;357:28-38. On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone )

PROacRve:)Risk)of)macrovascular)events)with)pioglitazone) Time to primary endpoint* in patients with type 2 diabetes and existing macrovascular disease with pioglitazone vs placebo (n=5238) 25 Pioglitazone (514 events) Placebo (572 events) Proportion of events (%) 20 15 10 5 HR=0.90 (p=ns) 0 0 6 12 18 24 30 36 Time from randomisation (months) Number at risk Pioglitazone 2488 2373 2302 2218 2146 348 Placebo 2530 2413 2317 2215 2122 345 *Death from any cause, non-fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, leg amputation, coronary revascularisation, or revascularisation of the leg. Dormandy J, et al. Lancet. 2005;366:1279-89.

Summary)of)literature:)hazard)raRos)for)cardiovascular) events)with)glitazones) Rosiglitazone Hazard Ratio/Odds Ratio Meta-analysis Nissen et al. 1 Meta-analysis Krall 2 Meta-analysis FDA 3 Meta-analysis GSK 4 Data from Nissen + RECORD 5 Meta-analysis Singh 6 Myocardial Infarction (OR) Cardiovascular Death (OR) Myocardial Infarction (OR) Myocardial Ischaemia (OR) Myocardial Ischaemia (HR) Myocardial Infarction (OR) Cardiovascular Death (OR) Myocardial Infarction (HR) 1.07 1.43 1.38 1.4 1.31 1.24 1.42 1.64 Pioglitazone PROactive 7 Composite Primary Endpoint* (HR) 0.90 MI, Stroke* and Death (HR) 0.84 PROactive MI-Subgroup 8 Myocardial Infarction (HR) 0.72 Meta-analysis Lincoff et al 9 MI, Stroke and Death (HR) 0.82 *Defined as a composite of all-cause mortality, non-fatal MI (including silent 0 1 2 MI), stroke, acute coronary syndrome, endovascular, or surgical intervention in Glitazones better Glitazones worse the coronary or leg arteries and amputation above the ankle. vs control vs control On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone ) 1. Nissen SE, et al. NEJM. 2007;356:2457-71. 2. Krall RL. Lancet. 2007;369:1995-6. 3. FDA-Hearing July 30, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/transcripts/2007-4308t1-part1.pdf. Accessed: July 27, 2010. 4. Avandia. Summary of Product Characteristics. 5. Bracken MB. N Engl J Med. 2007;357:937-8. 6. Singh S, et al. JAMA. 2007;298:1189-95. 7. Dormandy JA et al. Lancet. 2005;366:1279-89. 8. Erdmann E, et al. JACC. 2007;49:1772-80. 9. Lincoff AM, et al. JAMA. 2007;298;1180-8.

Pioglitazone)is)associated)with)a)lower)risk)of)heart)failure) and)death)than)rosiglitazone:)retrospecrve)cohort)study)(1))) Risk of adverse cardiovascular events among patients with type 2 diabetes treated with pioglitazone or rosiglitazone Events in pioglitazone patients n =16,951 Events in rosiglitazone patients n =22,785 Primary outcome 895 1563 Secondary outcomes Heart failure 461 869 Myocardial infarction 273 425 Death 377 645 Unadjusted hazard ratio (95% CI) 0.81 (0.74 0.87) 0.75 (0.67 0.84) 0.91 (0.78 1.06) 0.82 (0.73 0.94) Adjusted hazard ratio* (95% CI) 0.83 (0.76 0.90) 0.77 (0.69 0.87) 0.95 (0.81 1.11) 0.86 (0.75 0.98) *Cox proportional hazards model estimates adjusted for age, sex, duration of diabetes, residence in long-term care facility, socioeconomic status, year of cohort entry, Charlson comorbidity index, no. drugs in year before entry, history of renal disease or hospital admission for CV events, previous drug use Composite of death or hospital admission for either acute myocardial infarction or heart failure Juurlink DN, et al. BMJ. 2009;339:b2942. On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone )

Pioglitazone)and)rosiglitazone)are)associated)with)a)similar) risk)of)adverse)cv)outcomes:)retrospecrve)cohort)study)(2))) Event rates for CV outcomes and all-cause death in matched patients Primary composite outcome* Rosiglitazone (n=14,469) Pioglitazone (n=14,469) Patients with events, n (%) 602 (4.16) 599 (4.14) Event rate per 1000 person-years 26.38 25.76 Hazard ratio (95% CI) 1.03 (0.91-1.15), NS Reference Acute myocardial infaction Patients with events, n 120 139 Event rate per 1000 person-years 6.18 6.74 Acute heart failure Patients with events, n 289 261 Event rate per 1000 person-years 13.23 11.86 Death Patients with events, n 217 217 Event rate per 1000 person-years 11.44 11.22 *Acute myocardial infarction, acute heart failure and death. Includes 24 and 18 patients in the rosiglitazone and pioglitazone groups who had both acute myocardial infarction and acute heart failure. NS: non-significant. Wertz DA, et al. Circ Cardiovasc Qual Outcomes. 2010;3(5):538-45. On 23 September 2010, the European Medicines Agency recommended suspension of marketing authorisation for rosiglitazone )

FDA)guidance)on)CV)safety) In)December&2008,)the)FDA)recommended)that)new)drugs)for)type)2)diabetes) must)generate)data)demonstrarng)they)are)not)associated)with)an)unacceptable) increase)in)cv&risk& Phase)2)and)3)studies)need)to)be)designed)to)allow)reliable)meta<analysis&of&CV& events& Independent)blinded)adjudicaRon)commiéee)for)CV)events)which)should) include)cardiovascular&mortality,&myocardial&infarc'on,&and&stroke,)and)can) include)hospitalizaron)for)acute)coronary)syndrome)urgent)revascularisaron) procedures,)and)possibly)other)endpoints) Include)high<risk&pa'ents& FDA. Guidance for Industry. Diabetes Mellitus Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. December 2008. Available at: http://www.fda.gov/downloads/drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

AddiRonal)risk)factors)in)paRents)with)type)2)diabetes) Prevalence of risk factors in patients with type 2 diabetes Patients (%) with risk factor 70 60 50 40 30 20 10 63 67 45 22 0 Hypertension* Dyslipidaemia** BMI 30 kg/m 2 Cigarette smoking *Hypertension was defined as blood pressure 140/90 mmhg or receiving antihypertensive medication **Dyslipidaemia was defined as LDL cholesterol 130 mg/dl or receiving lipid-lowering medication Harris MI. Diabetes Care. 2000;23:754-8.

Impact)of)SBP)on)microvascular)and)macrovascular) complicarons)of)type)2)diabetes:)ukpds) Adjusted incidence/1,000 person-years (%, 95% CI) 50 40 30 20 10 Myocardial infarction Microvascular endpoints 0 110 120 130 140 150 160 170 Updated mean SBP (mmhg) Adler AI, et al. BMJ. 2000;321:412-9.

% mortality Tight)blood)pressure)control)reduces)complicaRons) in)diabetes:)ukpds)hypertension)substudy) 40 30 20 10 Diabetes-related deaths 32%)risk)reducRon)) p<0.02 Tight control with captopril or atenolol: mean BP 144/82 mmhg Less tight control: mean BP 154/87 mmhg 0 0 1 2 3 4 5 6 7 8 9 Years Microvascular disease Stroke % with events 20 15 10 5 37%)risk)reducRon)) p<0.01 20 15 10 5 44%)risk)reducRon)) p=0.013 0 0 1 2 3 4 5 6 7 8 9 Years 0 0 1 2 3 4 5 6 7 8 9 Years UKPDS Group. BMJ. 1998;317:703-13.

Hypertension)treatment)reduces)CV)events) in)diabetes:)hot)study) 30 All patients (n=18,790) 24.4 Diabetes (n=1501) 43% risk reduction p<0.005 CV events per 1000 patient-years 20 10 9.9 10.0 9.3 18.6 11.9 0 90 85 80 90 85 80 Target diastolic BP (mmhg) Target diastolic BP (mmhg) CV: cardiovascular Hansson L, et al. Lancet. 1998;351:1755-62.

ACCORD:)Intensive)blood)pressure)control)does)not) reduce)the)risk)of)fatal/non>fatal)major)cv)events) Primary outcome 1.0 Intensive Standard 0.2 p=0.20 Proportion with event 0.8 0.6 0.4 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 0.0 0 1 2 3 4 5 6 7 8 Years No. at risk Intensive 2362 2273 2182 2117 1770 1080 298 175 80 Standard 2371 2274 2196 2120 1793 1127 358 195 108 *Nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes ACCORD. New Engl J Med. 2010;362:1575-85.

Impact)of)LDL)reducRon)on)macrovascular)complicaRons) in)type)2)diabetes:)results)from)starn)trials 1>5) Patients with CHD event (mean %) 50 45 40 35 30 25 20 15 10 Diabetes 2º prevention HPS CHD (Tx) Diabetes 1º prevention HPS CHD (PL) 4S (Tx) LIPID (Tx) LIPID (PL) CARE (PL) CARE (Tx) 5 CARDS (Tx) CARDS (PL) HPS 1º (Tx) 0 50 70 90 110 130 150 170 190 210 Mean LDL-C (mg/dl) 4S (PL) 1. Colhoun HM, et al. Lancet. 2004;364:685-96. 2. Collins R, et al. Lancet. 2003;361:2005-16. 3. Keech A, et al. Diabetes Care. 2003;26:2713-21. 4. Goldberg RB, et al. Circulation. 1998;98:2513-9. 5. Pyörälä K, et al. Diabetes Care. 1997;20:614-20.

Lipid>lowering)therapy)is)effecRve)for)the)prevenRon) of)macrovascular)events)in)diabetes)parents:)hps) Effect of simvastatin on the percentage of participants with diabetes having major vascular events (n=5963) 30 Placebo-allocated RelaRve)risk)>22%)(95%)CI)>13)to)>30),)p<0.0001 Simvastatin-allocated Major vascular events (%) 25 20 15 10 5 0 0 1 2 3 4 5 6 Years of follow-up Benefit (SE) per 1000 allocated simvastatin -1 (6) 13 (8) 34 (9) 47 (10) 51 (15) 58 (48) Collins R, et al. Lancet. 2003;361:2005-16.

Lipid>lowering)therapy)is)effecRve)for)the)prevenRon)of) macrovascular)events)in)type)2)diabetes)parents:)cards) Effect of atorvastatin on the percentage of participants with type 2 diabetes having major cardiovascular events (n=2838) 20 Placebo Atorvastatin RelaRve)risk)>37%)(95%)CI)>52)to)>17),)p=0.001 Cumulative hazard (%) 15 10 5 Number at risk Placebo Atorvastatin 0 0 1 2 3 4 4.75 1410 1428 1351 1392 Years of follow-up 1306 1361 1022 1074 651 694 305 328 Colhoun HM, et al. Lancet. 2004;364:685-96.

CARDS:)AtorvastaRn)treatment)may)reduce)the)risk) of)non>haemorrhagic)stroke)in)type)2)diabetes) Treatment cumulative hazard estimates for time to stroke 4 Atorvastatin Placebo Cumulative hazard (%) 3 2 1 0 Risk reduction (95% CI) =48% (31%, 89%), p=0.016 0 1 2 3 4 4.75 Years from randomisation Number at risk Atorvastatin 1428 1401 1377 1093 714 343 Placebo 1410 1369 1341 1061 676 320 Hitman GA, et al. Diabetic Med. 2007;24:1313-21.

Prevalence)of)diabetes)increases)progressively)) with)increasing)bmi) 30 25.6 Patients with diabetes (%) 20 10 4.1 7.3 14.9 0 Normal BMI <25 (n=84,469) Overweight BMI 25-29.9 (n=70,231) Obese, Class 2 BMI 30-39.9 (n=35,767) Obese, Class 3 BMI 40 (n=4538) Units BMI = kg/m 2 Mokdad AH, et al. JAMA. 2003;289:76-9.

Modest)weight)reducRon)(5 10%):)benefits)for) increasing)life)expectancy) Guidelines recommend lifestyle interventions to promote weight loss and increase physical activity as an important part of diabetes management 1,2 Life expectancy from diagnosis (years) 16 15 14 13 12 11 10 9 8 7 Shaded area = 95% CI In a retrospective study, overweight patients with newly diagnosed diabetes who lost 10 kg in their first year of management, were estimated to gain a further 4 years of life 3 Graph illustrates life expectancy with different degrees of weight loss over the first year in patients with type 2 diabetes and BMI >25 kg/m 2 0 2 4 6 8 10 12 14 16 Weight loss in first 12 months (kg) 1. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases. Eur Heart J. 2007;28:88-136. 2. Nathan DM, et al. Diabetologia. 2009;52:17-306. 3. Lean ME, et al. Diabet Med. 1990;7:228-33.

STENO>2:)MulRfactorial)management)significantly) reduces)risk)of)cardiovascular)events)in)type)2)diabetes) 80 Primary composite endpoint* (%) 70 60 50 40 30 20 10 n=160 Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%) P=0.007 53% risk reduction (Intensive vs Conventional Therapy) p=0.01 Conventional therapy Intensive therapy 0 0 1 2 3 4 6 7 8 9 Time of follow-up (years) In)addiRon)to) 50%)relaRve)risk)reducRon)in)the)primary)composite)endpoint,)a)sustained)benefit)on)CV) events)was)also)observed)in)the)intensive)management)group)over)an)addironal)5.5)years 2 ) * Death from CV causes, non-fatal MI, CABG, PCI, non-fatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease 1. Gaede P, et al. N Engl J Med. 2003;348:383-93. 2. Gaede P, et al. N Engl J Med. 2008;358(6):580-91.

Effect)of)combined)glucose>)and)blood)pressure> lowering)on)complicarons)of)type)2)diabetes:) ADVANCE) Risk of complications in patients receiving intensive glucose- or blood pressure-lowering therapy or both versus standard therapy Major microvascular events 0.81 (0.68-0.97) Major renal events 0.72 (0.65-0.81) HR (95% CI)* 0.85 (0.72-1.02) 0.83 (0.69-0.99) Major macrovascular events Death from any cause IG: intensive glucose; P/I: perindopril/ indapamide; SG: standard glucose; HR: hazard ratio *Reference group = SG + placebo 0.2 0.4 0.6 0.8 1.0 1.2 Decreased risk of mortality vs standard therapy Zoungas S, et al. Diabetes Care. 2009;32(11):2068-74. 0.77 (0.69-0.85) 0.88 (0.79-0.97) 0.92 (0.77-1.10) 0.87 (0.73-1.04) 0.96 (0.81-1.14) 0.82 (0.68-0.99) 0.87 (0.72-1.04) 0.96 (0.80-1.15) IG + P/I SG + P/I IG + placebo

Current)risk)factor)management)in)type)2)diabetes) parents)is)suboprmal:)duty)registry) ProporRon)of)subjects)receiving)treatment)and)meeRng)guideline>based)targets)for) glycaemia,)arterial)hypertension)and)dyslipidaemia)in)germany) People with diagnosed T2D (%) 100 80 60 40 20 86.0 Treatment 74.1 33.2 45.9 Achieving target 7.6 15.8 (n=51,053)) 0 Glucoselowering therapy Antihypertensive therapy Lipidlowering therapy HbA 1c level (<7.0%) BP (<130/80 mmhg) LDL-C (<100 mg/dl) (<2.6 mmol/l) Berthold HK, et al. Deutsches Ärzteblatt. 2007;104:A861-2.

Steno>2:)εντατικοποιημένη)vs)συμβατικής)θεραπείας)και) ποσοστό)των)ασθενών)που)επιτυγχάνουν)τους)στόχους) Ποσοστό&ασθενών&που&επέτυχε&τους& στόχους&σε&διάστημα&&7.8&έτη&(%) & 80 70 60 50 40 30 20 10 0 P"=&0.06& HbA 1c & <&6.5%& Εντατική&θεραπεία&&& n&=&67& P"<&0.001& Χοληστερόλη& <&175&mg/dl& P"=&0.19& Τριγλυκερίδια& <&150&mg/dl& Συμβατική&θεραπεία& n&=&63& P"=&0.001& Συστολική&ΑΠ& <&130&mm&Hg& P"=&0.21& Διαστολική&ΑΠ& <&80&mmHg& Προσαρμογή&από&&Gaede&P,&et"al.&&N"Engl"J"Med"&2003;&348:383 393.&

CVD)is)the)leading)cause)of)death)worldwide)) in)people)over)60)years) Top 5 causes of death by age category Global Deaths in 2002 (x1000) 12000 10000 8000 6000 4000 2000 0 Self Injury Accidents TB CVD HIV Diabetes Lung Cancers <60 years old 60 years old LRTI COPD CVD The increase in population of people over 60 years will result in increased incidence of CVD Adapted from WHO. The Atlas of Heart Disease and Stroke 2004. Bonow RO et al. Circulation 2002;106:1602-5.

) Diabetes)is)a)CV)Risk)Factor) 60 Men 60 Women Mortality Rate Per 1000 50 40 30 20 10 Diabetes No Diabetes 2x Mortality Rate Per 1000 50 40 30 20 10 4-5x 0 0-3 4-7 8-11 12-15 16-19 20-23 0 0-3 4-7 8-11 12-15 16-19 20-23 Duration of Follow-up (Years) Duration of Follow-up (Years) Krolewski AS, et al. Evolving natural history of coronary disease in diabetes mellitus. Am J Med 1991;90(Supp 2A):56S-61S.!

RelaRve)Risk)of)CVD)in)Diabetes:)Framingham)Heart)Study) Any CVD event Stroke Intermittent claudication Cardiac failure CAD MI Angina pectoris Sudden death Coronary mortality 0 1 2 3 4 5 6 *P<0.001; P<0.05; P<0.01; P<0.1 Age-adjusted risk ratio * * * * * Male Female Kannel WB, et al. Am Heart J 1990;120:672-676.

)Cardiovascular)Death).Oasis)study) 0.20 0.15 Diabetes/CVD +, (n = 1,148) Diabetes/CVD -, (n = 569) No Diabetes/CVD +, (n = 3,503) No Diabetes/CVD -, (n = 2,796) RR = 2.85 (2.30-3.53) Event Rate 0.10 0.05 0.0 RR = 1.71 (1.41-2.06) RR = 1.71 (1.25-2.33) RR = 1.00 3 6 9 12 15 18 21 24 Months Malmberg K, et al. Circulation. 2000;102:1014-1019.

Μεγαλύτερος)κίνδυνος)θανάτου)για)ασθενείς)με)ΣΔ)και) έναν)παράγοντα)κινδύνου)έναντι)ατόμων)με)τρεις) 140& 120& Diabetes& No&diabetes& Age<adjusted&CVD& death&rate&per& 10,000&person<years& 100& 80& 60& 40& 20& 0& None& One&only& Two&only& All&three& Risk&factors& *Serum&cholesterol&>200&mg/dl,&smoking,&systolic&blood&pressure&>120&mmHg& Adapted&from&Stamler&J&et&al&Diabetes"Care"1993;16:434<444.&

Metabolic)Staging)of) Type)2)Diabetes) Peripheral insulin resistance Hyperinsulinemia Impaired glucose tolerance Defective glucorecognition Early diabetes β-cell failure Late diabetes Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

The)ConRnuum)of)Cardiovascular)Risk)in)Type)2) Diabetes) American Diabetes Association Diabetes Care 26:3160-3167 (2003). Tsao PS et al Arterioscler Thromb Vasc Biol 18:947-953 (1998). Hsueh WA et al Am J Med 105(1A):4S-14S (1998). American Diabetes Association Diabetes Care 21:310-314 (1998).

Natural)History)of)IGT) Normal Impaired glucose tolerance (IGT) After 10 years 33% 33% IGT 33% Diabetes

) Η)διαταραχή)ανοχής)γλυκόζης)είναι)παράγων) καρδιαγγειακού)κινδύνου.funagata)diabetes)study) 1.00 0.99 0.98 0.97 Cumulative Cardiovascular Survival 1.00 0.98 0.96 0.96 0.94 0.95 Normal Normal IGT (2 hr PG 140-200) 0.92 IFG (FPG 110-126) 0.94 DM (2 hr PG >200) DM (FPG >126) 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Year Year Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. Diabetes Care 1999;22:920-4.!

IGT)και&Επιπλοκές)από)τα)Μεγάλα)Αγγεία) (Μακροαγγειοπάθεια)" Η IGT, όπως έχει ορισθεί από τις οδηγίες του Παγκόσµιου Οργανισµού Υγείας (WHO) (2h-OGTT), είναι ένας δείκτης κινδύνου για επιπλοκές από τα µεγάλα αγγεία. 2 Αναλογία κινδύνου 1,75 1,5 1,25 Γνωστός διαβήτης IGT IFG 1 Καρδιαγγειακή Στεφανιαία νόσος νόσος Εγκεφαλικό επεισόδιο Όλες οι αιτίες IFG: Διαταραγµένη γλυκόζη νηστείας Πηγή: DECODE study group: Arch Intern Med 161: 397-404, 2001.

DaQing F-DPS DPP-US BMI baseline Malmo BMI FU Japan Diabetes Research and Clinical Practice 2005; 67: 152 162

Σε)ποιους)απευθύνεται)η)παρέμβαση;) IDF consensus on prevention of type 2 diabetes 1. &IGT,&IFG&& 2. Στις&ομάδες&αυξημένου&κινδύνου:) & )«OpportunisRc)screening»& Ηλικία)>)45)ετών) Περίμετρος)μέσης) Γυναίκες)με)ιστορικό)διαβήτη)κύησης) ΒΜΙ)>)25) Οικογενειακό)ιστορικό)ΣΔ) Παράγοντες)κινδύνου)για)ΚΑΝ) Πληθυσμοί)με)αυξημένο)κίνδυνο)εμφάνισης)ΣΔ) 3.Στο&γενικό&πληθυσμό;& International Journal of Clinical Practice 2007; 10: 1773-1775

Hyperglycaemia Oxidative stress Thrombosis Endothelium Adhesion molecules E n d o t h e l i a l D y s f u n c t i o n Atherosclerosis Breakfast Lunch Dinner

Η)μεταγευματική)γλυκόζη)συνδέεται)με)τη)θνητότητα)) ) DIS,"Diabetologia"1996"39:"155761583"

Ο)σχετικός)κίνδυνος)θανάτου)αυξάνει)με)τη))2>ωρη) μεταγευματική)γλυκόζη))ανεξάρτητα)από)τα)επίπεδα)της) γλυκόζης)νηστείας)) 2.5 2.0 Hazard ratio 1.5 1.0 0.5 0.0 <6.1 6.1 6.9 ³7.0 Fasting plasma glucose (mmol/l) <8 7.) ³11.1 7.8 11.0 Adjusted for age, center, sex DECODE Study Group. Lancet 1999;354:617 621

1.2& )Η)μεταγευματική)υπεργλυκαιμία)και)όχι)η) προγευματική)γλυκόζη)σχετίζεται))με)την)καν) 1.0& 0.8& 0.6& Log&rela've&risk&& 0.4& 0.2& 0& <0.2& <0.4& )Fas'ng&level& &Postchallenge&level& & <0.6& <0.8& 50& 75& 100& 125& 150& 175& 200& Blood&glucose&level,&mg/dl& Levitan&E.&Arch"Intern"Med&2004;164(19):2147.&Copyright& &2004,& American&Medical&Associa'on.&All&rights&reserved&&

Η)μεταγευματική)υπεργλυκαιμία)ανεξάρτητος) παράγοντας)για)καν) ) Model Hazard ratio for 3 rd tertile versus 1 st and 2 nd (95% CI) Men Women Fasting plasma glucose 0.73 (0.35 1.54) 2.34 (0.66 8.20) Postmeal glucose (2 hours after lunch) 2.12 (1.04 4.32) 5.54 (1.45 21.20)* HbA 1c 1.11 (0.55 2.21) 1.35 (0.43 4.26) CI)=)confidence)interval) HbA 1c )=)glycated)haemoglobin) ) *P<0.01)for)comparison)between)women)and)men)(post>lunch)values)) Adapted&from&Cavalot&F.&J"Clin"Endocrin"Metab&2006;91:813.&& Copyright&2006,&The&Endocrine&Society&

& CVD)mortality)risk)extends)below)the)threshold)for) Postmeal&hyperglycaemia&is&common&in&individuals& without&diagnosed&diabetes& diabetes) Number&of&subjects& Diabetes&threshold& Hazard&ra'o&(95%&CI)& CI)=)confidence)interval) 2<hour&plasma&glucose&(mmol/l)& DECODE&Study&Group.&Diabetes"Care &2003;26(3):688.&Copyright& & 2003&American&Diabetes&Associa'on.&Reprinted&with&permission&from& The&American&Diabetes&Associa'on&&

ΜΑGE&mg/dL& Risk&of&complica'ons&

Οξεία)υπεργλυκαιμία)και)διαβητικές)επιπλοκές) Στρες αγγειακού τοιχώµατος Γλυκόζη FFA, Λιπίδια Αθηρωµάτωση

ΣΔ)και)ΑΕΕ)

Παθοφυσιολογική)συσχέτιση) Εγκεφαλική ισχαιµία Υπεργλυκαιμία& Αναερόβιος µεταβολισµός Ελεύθερες ρίζες Παραγωγή γαλακτικού / Η + Ενδονουκλεάσες Γλουταµικό Μιτοχονδριακή βλάβη Ενδοκυττάριο Ca +2 Μη αναστρέψιµη βλάβη νευρικού κυττάρου Journal)of)Clinical)Neuroscience)9:)618>626,)2002)

Ενδονοσοκομειακή)πορεία) ΣΔ: 1,5-3 φορές µεγαλύτερος κίνδυνος έναντι γενικού πληθυσµού ΣΔ : ηλικία < 55 ετών δεκαπλάσιος ο κίνδυνος για ΑΕΕ Μεγαλύτερος χρόνος νοσηλείας Υπολειπόµενη νευρολογική και λειτουργική βλάβη µεγαλύτερη Κίνδυνος θανάτου µεγαλύτερος Diabetologia 1995; 30: 736 43.Diabetes Care 2005; 28: 355 9.&Diabetes Care 1993; 16: 434 44. Diabetes Care 1999;22: 1077-83. Stroke 1996; 27: 210 5. Stroke 2003; 344: 688 94,&Stroke 1997; 28:1913 8.

Μετέπειτα)εξωνοσοκομειακή)πορεία) Θνητότητα διπλάσια στους ασθενείς µε ΣΔ ένα χρόνο µετά την εµφάνιση του ΑΕΕ έναντι ατόµων χωρίς ΣΔ Πέντε χρόνια µετά το ΑΕΕ µόνο το 1/5 των διαβητικών επιβιώνει)) ) Διπλάσιος κίνδυνος επανεµφάνισης ΑΕΕ ) Diabet Med 1994; 11: 678 84. Diabetologia 1990; 33: 244 9. Stroke 1998; 29: 2491 500

Οξύ)ΑΕΕ)και)διαταραχές)μεταβολισμού)γλυκόζης) Φυσιολογική γλυκαιµία 19,7% Γνωστός διαβήτης 20,2% 19,7% Παροδική υπεργλυκαιµία 23,9% 16,4% IGT-IFG Νεοδιαγνωσµένος διαβήτης Diabetes Care 29:792 797, 2006 32%& Υπεργλυκαιµία 68%& 14% γνωστός ΣΔ 11,3% νεοδιαγνωσµένος ΣΔ 20% IGT 22,7% παροδική υπεργλυκαιµία Age and Ageing; 33: 71 77, 2004

Διαβητικοί)ασθενείς)με)ΑΕΕ:)πρόγνωση) &πιθανότητα&επανεμφάνισης&αεε&σε&σδ&μετά&από&30&ημέρες&(4,9%&έναντι&2,7%)&&&&&&&&&&&& Stroke"20;983 989,1989" &πιθανότητα&επανεμφάνισης&αεε&σε&σδ&μετά&από&δύο&έτη&(15.2%&έναντι&11,4%)&&&&&&&&&&&& Stroke"22;1556161,1996" " Ο&ΣΔ&διπλασιάζει&τον&κίνδυνο&επανεμφάνισης&ΑΕΕ&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Stroke"29;2491 500,1998" " 1&έτος&μετά&από&ΑΕΕ&διπλασιασμός&θνητότητας&στους&διαβητικούς&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Diabet"Med"11;"678 84,1994" " 5&έτη&μετά&από&ΑΕΕ&επιβιώνει&το&25%&των&διαβητικών&&&&&&&&&&&&&&&&&&&&&&&&&Diabetologia" 33;244 249,1990""

Μέτρηση)του)πάχους)του)έσω>μέσου)χιτώνα)της) καρωτίδας) Δείκτης)ενεργοποίησης)της) αθηρωματικής)διαδικασίας[1]) Αύξηση)τηςHbA1c)οδηγεί)σε)αύξηση) της)τιμής)ιμτ[2]) Οι)διαβητικοί)ασθενείς)εμφανίζουν) περισσότερο)εξωκρανιακή) αθηρωμάτωση[3]) 3)φορές)μεγαλύτερη)συχνότητα) εμφάνισης)α.ε.ε[4]) ) 1.Yosefy)Acta)Diabetol(2003)40:S358>S361) 2.Temelkova>Kurktsciev)et)al(2000).Diabetes) Care23:1830>1834) 3.Fabris)et)al(1994).Stroke)25:1133>1140) 4.Himmelmann)et)al(1988).Acta)Med)Scand) 224:439>443)

Diabetes)Increases)Risk)of)PAD) Prevalence)of)PAD)(%)) 25) 20) 15) 10) 5) 0) 12.5) Normal)Glucose) Tolerance) 19.9*) Impaired)Glucose)) Tolerance) 22.4*) Diabetes) N=1592) IGT)=)oral)glucose)tolerance)test)value) )140)mg/dL)but)<200)mg/dL) *P 0.05)vs)normal)glucose)tolerance) ) Lee)AJ,)et)al.)Br"J"Haematol.)1999;105:648>654.) )

Independent Risk Factors for PAD* Relative Risk vs the General Population Reduced Increased Diabetes 4.05 Smoking 2.55 Hypertension Total cholesterol (10 mg/dl) 1.10 1.51 * PAD diagnosis based on ABI <0.90. Newman AB, et al. Circulation. 1993;88:837-845

The)AcRvated)Platelet) Platelet)AcRvators) Blood) Thrombin) Thromboxane)A 2) Adenosine)diphosphate) Vessel)wall) Collagen) von)willebrand)factor) Platelet)Inhibitors) Nitric)oxide) Prostacyclin) " Ruggeri)ZM.)Nature"Medicine.)2002;8:1227>1234.)

Overlap)Between)PAD,)CAD,)and) CVD) CVD) CAD) 14.2%) 39.4%) 9.5%) PAD) 36.9%) PaRents)with)one)manifestaRon)) o{en)have)coexistent)disease)in)other)vascular)beds.) Bhaé)DL,)et)al.)REACH)InvesRgaRon.)Presented)at:)American)College)of)Cardiology)Annual)ScienRfic)Session;)March) 8,)2005;)Orlando,)FL.)Abstract)1127>96.)

Συμπέρασμα)1) )))) ))))Η)συμβολή)της)γλυκαιμικής)ρύθμισης)στην) πρόληψη)της)καρδιαγγειακής)νόσου)φαίνεται) ότι)είναι)ιδιαίτερα)σημαντική)στα)πρώτα) χρόνια)εμφάνισης)του)διαβήτη)και)απαιτεί)) μεγάλο)χρονικό)ορίζοντα)για)να)δώσει) σημαντικά)αποτελέσματα)(ukpds))

Συμπέρασμα)2) ))))) )))))Η)εντατική)γλυκαιμική)ρύθμιση)σε) μακροχρόνια)πάσχοντες)διαβητικούς)με) εγκατεστημένες)μικρο)και)μακροαγγειακές) επιπλοκές)δεν)συνδέεται)με)σημαντικά) ευνοïκά)αποτελέσματα)(accord>advance> VADT))