EVA, Metabolic Syndrome and rehabilitation

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1 Baltic Rehab Congress Tallinn 17th September 2010 EVA, Metabolic Syndrome and rehabilitation Peter Nilsson, MD, PhD Department of Clinical Sciences Lund University University Hospital, Malmo, Sweden

2 Metabolic syndrome Genes Lifestyle Increased risk of: cardiovascular disease, PCO type-2 diabetes, cognitive decline

Early Vascular Ageing (EVA): Atherosclerosis and arterial stiffening Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture Endothelial Dysfunction From

3 Early Vascular Ageing (EVA): Atherosclerosis and arterial stiffening Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture Endothelial Dysfunction From First Decade From Third Decade From Fourth Decade Growth of the Lipid Core Smooth Muscle and Collagen Thrombosis Nilsson PM, et al. J Hypertens 2008, Hypertension 2009 Minamino T, Circ Res 2007;100;15-26

4 Gerald Reaven, Banting Lecture 1988

5 Kylin E. Studien über das Hypertonie- Hyperglykemie- Hyperurikemiesyndrom. Zentralblatt für Innere Medizin 1923;7:105 Eskil Kylin ( ) Sarafidis P, Nilsson PM. J Hypertens 2005

6 Cornerstones in the Insulin Resistance Syndrome (IRS) or MetS Glucose visceral obesity hypertension liver steatosis dyslipidemia Insulin resistance endothelial dysfunction chronic inflammation Free Fatty Acids heredity (genes) lifestyle Insulin

7 Cumulative Hazard (%) Adverse Prognostic Implications of Cardiovascular Metabolic Syndrome Population-based observational study in 1209 men Metabolic syndrome present Metabolic syndrome absent Coronary heart disease mortality Cardiovascular disease mortality All-cause mortality RR (95% CI): 3.77 ( ) RR (95% CI): 3.55 ( ) RR (95% CI): 2.43 ( ) No. at risk metabolic syndrome Yes No Follow-up (years) Follow-up (years) Follow-up (years) Lakka H-M et al. JAMA. 2002;288:

8 The Metabolic syndrome: Time for a critical appraisal Joint Statement from the American Diabetes Association and the European Association for the Study of Diabetes Kahn R, Buse J, Ferrannini E, Stern M. Diabetes Care 2005;28:

9 New joint definition of MetS in 2009 Harmonizing the Metabolic Syndrome Based on the occurrence of three or more out of five of these risk factors: Elevated waist: population-specific cut-off levels Increased blood pressure: 130/85 mmhg Elevated glucose: 5.6 mmol/l Dyslipidaemia: Tg 1.7 mmol/l; HDL-C 1.0 in men and 1.3 mmol/l in women No priority for waist circumference alone Waist limits should be modified when applied to different ethnical groups Alberti KGMM, et al. Circulation, October, 2009

10 Treatment of MetS/IRS Lifestyle intervention is successful (DPS 2002, DPP 2002) Metformin is a well-proven drug that reduces mortality in overweight /obese subjects with DM2 (UKPDS 1998) and can prevent DM2 in IGT subjects (DPP 2002) Glitazones are tested for CVD and DM2 preventive effects with mixed results (Pro-Active, DREAM, RECORD) Antihypertensive drugs should be used without further impairing insulin sensitivity or worsening of metabolic abnormalities

11 Healthy food choices: Mediterranean Diet

13 Increased use of natural anti-oxidants

14 Smoking cessation always of great importance! Group sessions Social support Drugs: - NRT - Bupropion - Varenicline INTERHEART study, Lancet 2006

15 Lifestyle intervention for cardiovascular risk reduction in the primary health care setting: 3-year follow-up of the Björknäs study Margareta Eriksson º ¹ ², Carl-Johan Westborg º, Paul W Franks ², Mats Eliasson ² ³ Björknäs Primary Health Care Centre, Boden Sweden, ¹ Department of Community Medicine and Rehabilitation, Umeå University, Sweden, ² Department of Public Health and Clinical Medicine, Umeå University, Sweden, ³ Department of Medicine, Sunderby Hospital, Luleå, Sweden margareta.eriksson@nll.se Eriksson MK, et al. PLoS One. 2009;4(4):e5195.

16 Norrbotten, Sweden Björknäs PHC center in Boden

17 2. Outcomes measures Primary outcomes: Changes in anthropometry, maximal oxygen uptake, health-related quality of life and self-reported physical activity Secondary outcomes: Changes in blood pressure and metabolic variables

18 4. Time axis of the study Intervention Follow-up meetings for the intervention group monthly quarterly semi-annually 0 3 months 1 year 2 year 3 year Examinations

19 5. Intervention I. Exercise Three weekly group sessions of supervised progressive exercise training during the first 3 months. Water aerobics minutes Nordic walking / brisk walking minutes Interval training on a bicycle ergometer minutes and circuit-type resistance training minutes For optimal intensity: Borg RPE Scale % of maximal oxygen uptake

20 6. Intervention II. Diet counselling Five 20-min long group meetings with a dietician Written and verbal information In accordance with the Nordic recommendation In nutrition (NNR) III. Follow-up meetings regularly Led by a physiotherapist or a dietician Strategies used based on the stage.of-change model of behavioural change

Participants flow 340 eligible individuals were invited, with Dm, HT or MetS 177 individuals (52%) accepted to participate 151 were randomized, 76 to the control group and 75 to the

21 Participants flow 340 eligible individuals were invited, with Dm, HT or MetS 177 individuals (52%) accepted to participate 151 were randomized, 76 to the control group and 75 to the intervention group 145 were included in Intention-to-treat analyses 74 in the control group and 71 in the intervention group 120 subjects fullfilled the 3-year follow-up. Lost to follow-up18% 21

22 Changes in waist circumference (n=120) Control Intervention *** *** ** *** Changes between groups at independent t-tests * p< 0.05, ** p< 0.01, *** p <

Clinical measurements after 3 yrs (ITT n=145) Significant difference between groups: Decrease in waist circumference 2.2 cm Decrease in waist to hip ratio 0.

23 Clinical measurements after 3 yrs (ITT n=145) Significant difference between groups: Decrease in waist circumference 2.2 cm Decrease in waist to hip ratio 0.02 Reduction in systolic blood pressure 5.1 mmhg Reduction in diastolic blood pressure 1.6 mmhg Increase in maximal oxygen uptake, VO₂ 0.1 l/m No significant difference between groups in: Weight or Body Mass Index (BMI) 23

24 (mmhg) (mmhg) Changes in blood pressure ITT n=145 Systolic bloodpressure Diastolic blood pressure p-value p-value: * * * * Time Baseline 3 months 1 year 2 years 3 years 82 Time Baseline 3 months 1 year 2 years 3 years Control group Intervention group Control group Intervention group 24

25 (VO₂ l/min) (VO₂ ml/kg/min) Changes in aerobic fitness ITT n=145 Maximal oxygen uptake Maximal oxygen uptake 2,6 31 2,5 ** p-value *** p-value ,4 29 2,3 28 2,2 2, ,9 Time 0 3 m m m m Control group Intervention group 23 Time 0 3 m m m m Control group Intervention group 25

26 Laboratory measurements after 3 yr No significant differences between groups in: Blood lipids Blood glucose, HbA1 c Impaired glucose tolerans: 24% in intervention group, 34% in control group Control group: One new case of diabetes 26

27 Proportion of group Proportion of group Total physical activity A 100% 90% 80% Control group - Total physical activity Repeateed measures p-value < % 90% 80% Intervention group - Total physical activity 70% 70% 60% 50% 40% 30% 20% Very active Moderatly active Minimally active Sedentary 60% 50% 40% 30% 20% Very active Moderatly active Minimally active Sedentary 10% 10% 0% Baseline 3 months 1 year 2 years 3 years 0% Baseline 3 months 1 year 2 years 3 years Study phase Study phase

28 Proportion of group Proportion of group Exercise C 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Control group - Exercise Baseline 3 months 1 year 2 years 3 years Study phase Repeated measures p-value < >60 min/d min/d <30 min/d None 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Interventiongroup - Exercise Baseline 3 montths 1 year 2 years 3 years Study phase >60 min/d min/d <30 min/d None

29 Conclusion An inexpensive prevention programme in the primary health care setting with focusing on physical activity and diet counselling and structured follow-up meetings can favourably influence several cardiovascular risk factors in high-risk subjects, which persists for up to three years.

30 Specific Drug Therapy One example Stroke secondary prevention

31 Three men that all died of stroke or its complications

32 Messerli F, N Engl J Med 1995;332:

33 Rehabilitation after CVD event Lifestyle intervention Evidence-based drug therapy Technical interventions Support-groups and active relatives Structures programmes for follow-up

Blood Pressure Lowering and Secondary Prevention of Stroke Trials of Antihypertensive Treatment in Patients With Previous Stroke or TIA 160 50 150 149 43% 40 Achieved SBP

34 Blood Pressure Lowering and Secondary Prevention of Stroke Trials of Antihypertensive Treatment in Patients With Previous Stroke or TIA % 40 Achieved SBP (mmhg) % % % Stroke reduction 120 PATS All Comb 5% Mono 5% PROF 0 PROGRESS Zanchetti et al. J Hypertens 2009; 27:

35 Effects of Blood Pressure Lowering on Fatal and Nonfatal Recurrent Stroke All Studies Trial BP Δ BP Odds Ratios (95% Cl) Recurrent Stroke/Patients All diuretics 153/ 91 Q=5.43 P=0.14 All RAS inhibitors Q=4.56 P= /8 4 FEVER* 160/9 3 Treated Control 9.6/ ( ) 356/ /4867 2P< / ( ) 1227/ 2P= / /1.8 66/ / 1232 All trials 147/8 6 Heterogeneity Q=32.2 P= *FEVER: Felodipine Event Reduction Study 5.1/ ( ) 1649/ 2P= Favors Favors Treatment Control 1916/ Liu et al, Hypertens Res 2009; 32:

Statins in Primary Prevention of Stroke Risk of stroke in four statin primary prevention trials Hazard Ratio [95% CI] WOSCOPS AFCAPS/TexCAPS MEGA JUPITER RR: 0.89 [0.53-1.51] RR: 0.

36 Statins in Primary Prevention of Stroke Risk of stroke in four statin primary prevention trials Hazard Ratio [95% CI] WOSCOPS AFCAPS/TexCAPS MEGA JUPITER RR: 0.89 [ ] RR: 0.82 [ ] RR: 0.83 [ ] RR: 0.52 [ ] All RR: 0.75 [ ]; p= Statin better Placebo better Everet et al. Circulation 2010; 121:

Statins in Secondary Prevention of Stroke: the SPARCL Study 205 centres worldwide Mean age 63 years Stroke or TIA documented 6 previous months 62% with HT and 17% DM-2 No previous CVD Antiplatelet

37 Statins in Secondary Prevention of Stroke: the SPARCL Study 205 centres worldwide Mean age 63 years Stroke or TIA documented 6 previous months 62% with HT and 17% DM-2 No previous CVD Antiplatelet therapy 94% LDL-C levels 100 mg/dl and 190 mg/dl 4,731 patients Double blind period Atorvastatin 80 mg/day Placebo Primary end-point: Time to first fatal and non-fatal stroke The SPARCL Investigators. N Engl J Med. 2006; 355:

38 Statins in Secondary Prevention of Stroke: SPARCL Study Cumulated incidence (%) 8 Fatal and non-fatal stroke Atorvastatin 80 mg Placebo RRR 16% 4 0 P= 0.03 Adjusted RR*= 0.84 [IC 95% ] Time (years) since randomization The SPARCL Investigators. N Engl J Med. 2006; 355:

39 Arterial wall Time course of Early Vascular Ageing (EVA) and possible intervention by Aggressive Decrease of Atherosclerosis Modifiers (ADAM) in CVD risk patients 100% damaged Period of early detection and successful regression ADAM (late stage) ADAM (earlier stage) EVA 100% normal normal vascular aging Time Nilsson PM, Laurent S. et al. Hypertension 2009

40 Summary The Metabolic syndrome (MetS) as a clinical entity has been recognised by clinicians for more than 80 years Even if MetS is not a perfect tool for research it can be used in clinical practice to find risk factor clusters The core effects of AH in MetS is the arterial stiffening and target organ damage, including EVA Lifestyle intervention is part of rehabilitation and synergistic with drug therapy PN 2010

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