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Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes

Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes. N Engl J Med 348:383-93, 2003 Peter Gæde, Pernille Vedel, Nicolai Larsen, Gunnar Jensen, Hans-Henrik Parving, and Oluf Pedersen . Background. The Steno-2 study was designed in 1990

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Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes

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  1. Multifactorial Intervention and Cardiovascular Disease in Patients with Type 2 Diabetes N Engl J Med 348:383-93, 2003 Peter Gæde, Pernille Vedel, Nicolai Larsen, Gunnar Jensen, Hans-Henrik Parving, and Oluf Pedersen STENO-2

  2. Background • The Steno-2 study was designed in 1990 • There was no evidence base for the treatment of type 2 diabetes • Some diabetes educators were suffering from therapeutic nihilism • Intervention studies including the UKPDS were ongoing STENO-2

  3. Steno-2:Idea and Frames • An attempt to validate the efficacy of • daily clinical practice, i.e. the • multifactorial treatment of type 2 • diabetes • High risk type 2 diabetes patients • A single center study • An organisation which allowed for • intensive intervention • Longterm intervention STENO-2

  4. Steno-2: Aim • To investigate the impact on microvascular and cardiovascular disorders of a target driven behaviour modification and polypharmacy as compared to a conventional multifactorial treatment of high-risk type 2 diabetic patients with the metabolic syndrome including microalbuminuria STENO-2

  5. Steno-2: Design • A PROBE design was applied, i.e. • a Prospective, Randomized, Open, Blinded Endpoint study • 160 patients with type 2 diabetes and the metabolic syndrome including microalbuminuria were with consealed randomization allocated conventional therapy at their GP’s or intensive care at Steno Diabetes Center Conventional group assigned to GPs 80 Microvascular Macrovascular n=160 Endpointexaminations 4 years 8 years 80 Intensive group assigned to Steno Diabetes Center STENO-2

  6. Steno-2:Microvascular endpoints after 4 yrs Number of patients developing/progressing in microvascular endpoint OVERALL A 50% RELATIVE RISK REDUCTION Nephropathy Conv - Int Retinopathy Conv - Int Neuropathy Conv - Int The Lancet 353;617-622, 1999 STENO-2

  7. 63% 70 61% 58% 53 % 60 50 40 30 20 10 0 cardiovascular nephropathy retinopathy autonomic disease neuropathy Steno-2: Relative risk reduction at year 7.8 Relative risk reduction in intensive therapy group STENO-2 N Engl J Med 348:383-93, 2003

  8. 160 patients stratified according to urinary albumin excretion rate and then randomly assigned to treatment groups 80 patients received conventional therapy 80 patients received intensive therapy 15 died 7 of CVD 5 of cancer 3 of other causes 12 died 7 of CVD 2 of cancer 3 of other causes 2 withdrew 1 withdrew 63 patients completed the study after 7.8 yrs 67 patients completed the study after 7.8 yrs STENO-2

  9. Steno-2:Baseline characteristics Conventional Intensive n=80 n=80 Gender (M/F) 56/24 63/17 Age (yrs) 55 55 Known DM (yrs) 6 6 Body mass index (kg/m2) 30 30 Haemoglobin A1c (%) 8.8 8.4 Fasting s - -cholesterol (mmol/l) 5.8 5.4 Blood pressure (mm Hg) 149/86 146/85 Albumin excretion rate (mg/24 h) 69 78 STENO-2

  10. The intensive-therapy group - what’s the difference? Individualised risk assessment Ambitious goal setting Focused behaviour modification More drugs/higher dose Continued patient education/motivation STENO-2

  11. Steno-2:Treatment goals Conventional * Intensive Haemoglobin A1c (%) <7.5 <6.5 F-s-cholesterol (mmol/l) <6.5 <4.5 F-s-triglycerides (mmol/l) <2.2 <1.7 Systolic BP (mm Hg) <160 <130 Diastolic BP (mm Hg) <95 <80 ACEi irrespective of BP No Yes No Yes Aspirin, primary prevention * Guidelines from the Danish Medical Association STENO-2

  12. Lifestyle change in the intensive-therapy group Patients and spouses were motivated to join smoking cessation courses Nicotine substitutes were given for free STENO-2

  13. Food advice to the intensive therapy-group Have some kind of seafood every day Cut down on animal fat STENO-2

  14. Food advice to the intensive-therapy group 5-6 servings of vegetables and fruits/day STENO-2

  15. Exercise advice to the intensive-therapy group Enjoy physical performance more than 150 min/week STENO-2

  16. p=0.58 p=0.02 p=0.13 p=0.09 LIFESTYLEPercentage of patients obtaining treatment goals for the intensive-therapy group after 7.8 yrs Saturated fat <10% E Exercise >150 min/week Fat intake <30% E Non-smokers Intensive Convent Intensive Convent Intensive Convent Intensive Convent STENO-2

  17. Higher intake of fish and vegetables/fruits in the intensive-therapy group after 7.8 yrs Conventional Intensive Vegetables (g/day) 100 160 Fruits (g/day) 125 265 Fish (times/week) 2 4 STENO-2

  18. Relative failures Daily exercise: More than difficult due to CVD and osteoarthritis Quit smoking: Unhealthy habits in middle-aged people are tough to eliminate and replace STENO-2

  19. Drug treatment: stepwise and target driven • Hyperglycaemia:Gliclazide • Metformin • Insulin • Dyslipidaemia:Statins • Fibrates • Hypertension: ACE-inhibitors • Angiotensin II receptor blockers • Diuretics • Calcium antagonists • Beta-blockers • Microalbuminuria:ACE-inibitors • Other CVD prevention:Aspirin • Folic acid = ’PolyPill’ plus insulin STENO-2

  20. Stepwise treatment of hyperglycaemia Gliclazide + NPH insulin BMI <27 Diet Gliclazide Gliclazide + Metformin Metformin + NPH insulin BMI ≥27 Metformin Diet Time STENO-2

  21. Stepwise approach to the treatment of hypertension Severity of hypertension Other ß-blocker Calcium antagonist Diuretics ACE inhibitor/Angiotensin II antagonist STENO-2

  22. Differences in drug treatment at the end of study Number of patients 70 Intensive Conventional 60 50 40 30 20 10 0 OHA Insulin Both ACE-I ARB Both Statin Aspirin Folic acid STENO-2

  23. Biochemical risk factors at year 7.8 in conventional (C) versus intensive (I) group • Haemoglobin A1c • Systolic BP • Diastolic BP • Total-cholesterol • LDL-cholesterol • Triglycerides • Urinary albumin 9.0 in C versus 7.9 % in I 146 versus 131 mm Hg 78 versus 73 mm Hg 5.6 versus 4.1 mmol/l 3.3 versus 2.1 mmol/l 3.0 versus 1.7 mmol/l 126 versus 26 mg/24h STENO-2

  24. Percentage of patients achieving treatment goals set for the intensive-therapy group at 7.8 yr HbA1c<6.5% Cholesterol <4.5 mM Triglycerides <1.7 mM Systolic BP <130 mm Hg Diastolic BP <80 mm Hg % p<0.0001 p=0.21 p=0.19 p=0.001 p=0.06 Int Conv Int Conv Int Conv Int Conv Int Conv STENO-2

  25. Steno-2:Endpoints at 7.8 years • Primary: Cardiovascular disease • Cardiovascular mortality • Non-fatal myocardial infarction • Coronary artery bypass graft • Non-fatal stroke • Revascularization • Amputation • Secondary: Microvascular disease • Progression to nephropathy • Development of/progression in retinopathy • Development of/progression in neuropathy STENO-2

  26. Primary composite cardiovascular endpoint 85 CVD events in 35 ’conventional’ patients (44%) 33 CVD events in 19 ’intensive’ patients (24%) Probability for primary endpoint Conventional Intensive Hazard ratio 0.47 (0.24 to 0.73); p=0.007 0 12 24 36 48 60 72 84 96 Months of follow-up STENO-2

  27. Steno-2: 85 CVD events in 35 ’conventional’ patients 33 CVD events in 19 ’intensive’ patients Number of events Vascular surgery Myocardial infarction PCI or CABG Amputation CVD death Stroke Intensive Conventional STENO-2

  28. Stroke 3 patients (4%) in the intensive and 11 patients (14%) in the conventional group had strokes during follow-up Number of strokes per patient (Recurrence rate) Total number of strokes Intensive Convent Intensive Convent STENO-2

  29. StrokeTime to first stroke Log-rank test: P=0.02 Hazard ratio 0.25 (0.07 – 0.89); p = 0.03 Conventional Probability for stroke (%) Intensive Months of follow-up STENO-2

  30. Myocardial infarctionTime to first MI Log-rank test P=0.08 25 Hazard ratio 0.41 (0.14-1.15); p = 0.09 20 Conventional 15 10 Probability for MI (%) Intensive 5 0 0 12 24 36 48 60 72 84 96 Months of follow-up STENO-2

  31. Coronary interventionsTime to first PCI or CABG Log-rank test P=0.07 25 Hazard ratio 0.40 (0.14 – 1.12); p =0.08 20 Conventional 15 Probability for intervetnion (%) 10 Intensive 5 0 0 12 24 36 48 60 72 84 96 Months of follow-up STENO-2

  32. Estimated impact of single risk factor interventions to reduce CVD in patients with type 2 diabetes • Relative risk 2-yr’s event • reduction rate • None …… 11.0 % • Cholesterol (down by 0.6 mmol/l) 25 %8.3 % • BP (down by 5/2 mm Hg) 27 % 6.0 % • HbA1c (down by 0.9 %)13 % 5.2 % • Aspirin 9 % 4.7 % • Cumulative relative risk reduction of about 57% Huang et al. Am J Med 2001;111:633-642 Turner R.C. BMJ 1998;316:823-828 He et al. JAMA 1999;282:2027-2034 Antitrombotic Trialits BMJ 2002;324:71-86 STENO-2

  33. Estimated impact of single risk factor interventions to reduce CVD in patients with type 2 diabetes • Relative risk 2-yr’s event • reduction rate • None …… 11.0 % • Cholesterol (down by 0.6 mmol/l) 25 %8.3 % • BP (down by 5/2 mm Hg) 27 % 6.0 % • HbA1c (down by 0.9 %)13 % 5.2 % • Aspirin 9 % 4.7 % • Cumulative relative risk reduction of about 57% Huang et al. Am J Med 2001;111:633-642 Turner R.C. BMJ 1998;316:823-828 He et al. JAMA 1999;282:2027-2034 Antitrombotic Trialits BMJ 2002;324:71-86 STENO-2

  34. Microvascular complications in Steno-2Accumulated incidence during 7.8 years Relative risk Nephropathy (NNT 4) 0.39 Retinopathy (NNT 5) 0.42 Auto. neuropathy (NNT 3) 0.37 1.09 Periph. neuropathy 1.0 0 0.5 1.5 2.0 2.5 In favor of intensive In favor of conventional STENO-2

  35. Steno-2:Kidney disease Patients who progressed to nephropathy P=0.003 ESRD (Dialysis) P=NS Intensive Conventional Intensive Conventional STENO-2

  36. Steno-2Eye complications Progression in retinopathy New retinopathy Blindness in one eye P=0.03 P=0.02 P=0.02 Number of patients Number of patients Intensive Intensive Conventional Conventional Intensive Conventional STENO-2

  37. Steno-2:Neuropathy Intensive n=67 Conventional n=63 p-value STENO-2

  38. Steno-2:Adverse effects? Polypharmacy? One patient in the intensive- therapy group had a bleeding gastric ulcer Hypoglycaemia? No difference Weight gain? No difference STENO-2

  39. Steno-2:Hypoglycaemia Intensive n=67 Conventional n=63 p-value At least one minor episode 39 42 NS At least one major episode 12 5 0.07 Major episode during insulin treatment 9 4 NS Data are number of patients STENO-2

  40. Steno-2: Weight gain/body composition Intensive n=67 Conventional n=63 p-value Average weight gain (kg) 2.0 3.1 0.49 Increase in waist (cm) Men 4 3 0.23 Women 5 6 0.81 Data are number of patients STENO-2

  41. Steno-2: Summary Compared with a conventional multifactorial treatment an intensive and target driven behaviour modelling and polypharmacy for 7.8 yrs induced an absolute risk reduction of 20% (RRR 0.53; NNT 4) in CVD in patients with type 2 DM and the metabolic syndrome incl. microalbuminuria The RRR’s found for microvascular events after 4 years were main- tained at a similar level after 7.8 years of intervention: nephropathy 61%, retinopathy 58% and autono- mic neuropathy 63% STENO-2

  42. ’The Steno-2 therapeutic package’ • Repetitive risk assessments • Ambitious treatment goals • Progressive and aggressive drug treatment • Proactive behaviour modelling • Continued patient education and motivation STENO-2

  43. Further information • Contact: • Professor Oluf Pedersen, MD, DMSCi • Principal Investigator of the Steno-2 Trial • Steno Diabetes Center • 2820 Gentofte, Copenhagen, • Denmark • oluf@steno.dk STENO-2

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