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ENGLISH COURSE: SYSTEMATIC REVIEW OF A META-ANALYSIS. Resident Doctor: Jai K. Daryanani Health Care Centre: San Andrés Torcal Zone II , Malaga Tutor: Dr Vicente Villatoro Jimenez SYSTEMATIC REVIEW Effect of intensive control of glucose on a meta-analysis of randomised controlled trials Kausik K Ray, Sreenivasa Rao Kondapally Seshasai*, Shanelle Wijesuriya*,Rupa Sivakumaran*, Sarah Nethercott*, David Preiss, Sebhat Erqou,Naveed Sattar Lancet 2009; 373: 1765–72 SYSTEMATIC REVIEW INTRODUCTION • DM II Risk factor for Cardiovascular. • Observational studies: + correlation between measures of glycaemic control and cardiovascular outcomes independent of risk factors • Randomised Control trials aimed to asses : Intensive Standard Clinical events Glucose VS Treatment Treatment Lengthens life INTRODUCTION • Meta-Analysis : 5 controlled clinical trials • Aimed to asses : CARDIOVASCULAR Intensive Standard EVENTS Glucose VS Treatment Treatment STROKE ALL CAUSE MORTALITY Model of Meta- Analysis: RANDOM EFFECTS META-ANALYSIS METHODS • DATA SOURCES: Medline January 1970 Cochrane Central to Embase January 2009 Cardiovascular Diseases Terms Related DIABETES VASCULAR OUTCOMES Glucose Diabetes HbA1c Mellitus METHODS • DATA SOURCES: • Search Provided 2439 ARTICLES!!!! • Further screened from inclusion (Titles/Abstracts/Full text/ combination) • Electronical search from Lists of Relevant articles including Meta-analysis and Reviews METHODS STUDY SELECTION CRITERIA INCLUSION: 1. DMII patients allocated randomly Intensive Therapy/ Standard regimen with glycaemic control measured by HbA1c. 2. Primary End-Point: CARDIOVASCULAR EVENTS: • Non fatal myocardial infarction • Coronary Heart Disease ( Fatal or Non Fatal) • Stroke • All cause of mortality 3. Stable individuals ONLY!! METHODS STUDY SELECTION EXCLUSION CRITERIA: ADOPT & RECORD RECORD DREAM UGDP STENO 2 KUMAMATO METHODS STUDY SELECTION 5 STUDYS fulfilled CRITERIA INCLUSION: • UKPDS: United Kingdom Prospective Diabetes Study • PROspective: Pioglitazone Clinical Trial In macrovascular events • ADVANCE: Action in Diabetes and Vascular Disease • VADT: Veterans Affairs Diabetes Trial • ACCORD: Action to Control Cardiovascular Risk in Diabetes Trial PARTICIPANTES: 33.040 METHODS STUDYS INTENSIVE STANDARD HbA1C at follow up UKPDS Sulfonylurea, insulin, or Metformin Standard Diet 7.9 % 7.0% PROactive 15-45mg oral Pioglitazone plus Current Medication current medication 7.6% 7.0% 30-120mg glicazide, with or Standard treatment without As per ADVANCE metformin,thiazolidienedion, Local guideline glinide, acarbose or insulin. 6.8% 7.3% Max dose Metformin with Half Dose of rosiglitazone(BMI>27) or Intensive VADT glimepiride&rosiglitazone Treatment (BMI>27)8.4% 6.9% ACCORD Metformin/Sulphonylurea/glinide/ Standard Thiazlindinedione/acarbose/insulin Treatment /combination 7.5% 6.4% DATA EXTRACTION • NUMBER OF EVENTS 3500 2892 3000 2500 2318 2000 1497 EVENTS 1500 1127 1000 500 0 NON FATAL MI CORONARY HD STROKE ALL CAUSE DATA EXTRACTION 1. Study investigators independently abstracted data in duplicate using a standard format from all relevant studies 2. Another investigator adjudged any discrepancies BASELINE CHARACTERISTICS 1. Age 2. HbA1c concentration 3. Blood Pressure 4. BMI 5. Absolute Number of Events PROactive (NFMI, Coronary Heart UKPDS ADVANCE disease, Stroke and all cause of Mortality) VADT 6. Heart failure ACCORD 7. Type of death UKPDS 8. HbA1c during follow up 9. Adverse events: Hypoglycaemia & Weight gain BASELINE CHARACTERISTICS STATISTICAL ANALISIS • UKPDS, ProAcive, ADVANCE Hazard Ratios & CI 95% • VADT & Accord provided absolute number events • We examined the relationship between intensive glucose control and standard therapy on the outcomes of interest • Statistical heterogeneity across trials was assessed with χ2 (p<0・1) and I2 statistics. • Absolute rates of every end point was : Absolute Nº Events Nº Person Years-follow up • Analyses were done with Stata V10.1 • RANDOM EFFECTS-MODEL META-ANALYSIS. STATISTICAL ANALISIS FUNDING SOURCE • No Funding Source • The author had full access to data and final responsibility for decision to submit for publication. RESULTS 33040 <1 y RESULTS • 4 Studies Macrovascular disease 32-100% • Proactive, Macrovascular disease Criteria eligibility • Participants Age; 53-66 years; >50% were men • LDL, Systolic BP, HbA1c concentration • Participants with Intensive treatment had a 0.9% mean HbA1C compared to Standard • There were 2.3 fewer events of myocardial infarction in the Intensive treatment and 2.9 fewer events of CHD for every 200 patients /5 years • STROKE & All cause Mortality were not Statistically different RESULTS RESULTS 0.83(0.75-0.93 Probability of Events of Non Fatal Myocardial Infarction with intensive/standard RESULTS 0.85(0.77-0.93 Probability of Events of Coronary Heart Disease with intensive/standard RESULTS Probability of Events of Stroke with intensive/standard RESULTS Probability of Events of All cause Mortality with intensive/standard RESULTS • Data for cardiovascular mortality and Non cardiovascular mortality restricted to 4 STUDIES of 28420 participants • UKPDS did not record data for Cardiovascular Mortality • Intensive therapy did NOT affect the TYPE OF DEATH • Patients with Intensive therapy had more hypoglycaemia episodes (2:1) • Patients with intensive therapy were a mean of 2.5 Kg heavier than those on Standard Treatment DISCUSSION • Meta-analysis shows cardiovascular benefit with the intensive treatments vs the standard. • Reduction of HbA1c of 0.9% resulted in: 1. 17% in events of Non fatal myocardial infarction 2. 15% in events of Coronary Heart Disease 3. Non significant 7% reduction in events of Stroke Did not affect all cause of Mortality DISCUSSION LIMITATIONS 1. Retrospective Research affected by METHODOLOGICAL, comprehensiveness and possibility of publication bias. 2. Due to different variety of studies, this meta-analysis can only report whether intensive treatment is safe and effective for reduction of macrovascular events 3. The study cant provide superiority of a specific glucose lowering regimen 4. Not Sufficient DATA available TO analyse the effects of Intensive treatment within various subgroups ( age, men vs women, duration diabetes, baseline HbA1c, comorbility) 5. Used ODDS Ratios vs Hazard Ratios, to enable data of all 5 studies . 6. Sensitivity analysis Random effects model DISCUSSION • This meta-analysis provides the effectiveness of glycaemic control for cardiovascular risk reduction, but doesn’t prove a clear benefit to all cause mortality. • LIPID treatment and BP reduction have strong evidence in reduction to all cause mortality in DM II patients. • Optimum methods to achieve glycaemic control need to be established, and guidelines drawn up with specific recommendations for reduction of HbA1c concentration.
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