Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 2015; published online March 17. http://dx.doi.org/10.1016/ S2213-8587(15)00044-3.
Novel Glycaemic Treatment Strategies and Cardiovascular Outcomes in Patients with or at Risk for Diabetes: A Meta-Analysis of Randomised Trials Supplementary Appendix 1
Search Strategies for MEDLINE Database: Ovid MEDLINE(R) <1946 to February 20 (Week 3) 2015> Search Strategy: 1 risk.mp. (1531525) 2 exp Heart Failure/ (88948) 3 exp heart failure/ or heart failure.mp. (134704) 4 exp Cardiomyopathy, Dilated/ (13211) 5 exp Cardiomyopathy, Dilated/ or Cardiomyopathy.mp. (52586) 6 exp cardiovascular disease/ or cardiovascular disease.mp. (1925769) 7 exp Diabetes Mellitus/ (320069) 8 exp Hemoglobin A, Glycosylated/ (23403) 9 exp Blood Glucose/ (130757) 10 (diabetes mellitus or type 2 or haemoglobin A1c or glycosylated or glycated or glucose).mp. (690811) 11 (glycemic control or glucose control or aggressive or intensive or tight).mp. (332393) 12 2 or 3 or 4 or 5 or 6 (1941704) 13 7 or 8 or 9 or 10 or 11 (1039340) 14 1 and 12 and 13 (65999) 15 limit 14 to randomized controlled trial (3899) 2
Appendix Figure 1. Funnel plot for heart failure stratified by anti-diabetic drug class/strategy. The outer dashed lines indicate the triangular confidence interval boundary within which 95% of studies are expected to lie in the absence of bias or heterogeneity. The dashed vertical line represents the summary treatment effect point estimate. A relative risk (RR) value of 1 represents the null treatment effect point estimate. 3
Appendix Figure 2. Funnel plot for MACE stratified by anti-diabetic drug class/strategy. The outer dashed lines indicate the triangular confidence interval boundary within which 95% of studies are expected to lie in the absence of bias or heterogeneity. The dashed vertical line represents the summary treatment effect point estimate. A relative risk (RR) value of 1 represents the null treatment effect point estimate. 4
Appendix Table 1. Definition of Heart Failure (HF) and Major Adverse Cardiovascular Events (MACE) Trial HF Definition MACE Definition Expanded MACE Definition UKPDS 33 (1998) 1 HF (not associated with MI), by clinical symptoms confirmed by Kerley B lines, rales, raised jugular venous pressure, or third heart sound Fatal and non-fatal MI Any diabetes-related endpoint (sudden death, glycaemic death, fatal or non-fatal MI, UA, HF, stroke, renal failure, amputation of at least one digit, vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction) PROactive (2005) 2-4 HF not needing or needing hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity Death, MI, or stroke Death, non-fatal MI (including silent MI), stroke, UA, coronary revascularization, peripheral artery revascularization, or limb amputation above the ankle ADOPT (2006) 5 Investigator-reported congestive HF Fatal and non-fatal MI Any fatal or non-fatal CV event (MI, CHD, stroke, HF, PAD) DREAM (2006) 6 Acute treatment for HF with at least two of the following criteria: typical signs and symptoms, typical radiological evidence, use of diuretics, vasodilators, or inotropes CV death, MI, or stroke CV death, MI, stroke, HF, arterial revascularization procedures, new angina with objective evidence of ischemia, or ventricular arrhythmia needing resuscitation ACCORD (2008) 7 Fatal HF or non-fatal hospitalization for congestive HF CV death, MI, or stroke NR ADVANCE (2008) 8 Investigator-reported congestive HF CV death, MI, or stroke Any fatal or non-fatal CV event (MI, CHD, stroke, HF) BARI2D (2009) 9 The occurrence of 1 or more of dyspnea on exertion, Death, MI, or stroke NR bilateral pedal edema, fatigue, orthopnea, and paroxysmal nocturnal dyspnea RECORD (2009) 10 Fatal HF and non-fatal HF hospitalization CV death, MI, or stroke CV death, MI, stroke, HF, or UA VADT (2009) 11 New or worsening congestive HF Fatal and non-fatal MI CV death, MI, stroke, new or worsening HF, arterial revascularization surgery, inoperable CHD, or amputation for ischemic gangrene ORIGIN (2012) 12 Hospitalization for congestive HF (new or recurrent) CV death, MI, or stroke CV death, MI, stroke, hospitalization for HF, or arterial revascularization EXAMINE (2013) 13, 14 Hospitalization for HF (new or recurrent) CV death, MI, or stroke Death, MI, stroke, hospitalization for HF, or urgent coronary revascularization for UA Look-AHEAD (2013) 15 Hospitalized congestive HF (new onset or worsened) CV death, MI, or stroke CV death, MI, stroke, or hospitalization for UA SAVOR-TIMI 53 (2013) 16 HF requiring hospitalization CV death, MI, or ischemic stroke CV death, MI, ischemic stroke, hospitalization for HF, coronary revascularization, or UA AleCardio (2014) 17 HF requiring hospitalization CV death, MI, or stroke CV death, MI, stroke, or hospitalization for UA Abbreviations: CHD: coronary heart disease; CV: cardiovascular; HF: heart failure; MI: myocardial infarction; NR: not reported; PAD: peripheral artery disease; UA: unstable angina. 5
Appendix Table 2. Trial Quality Metrics and Risk of Bias Trial Blinding Discontinued Drug/Strategy* (%) Lost to Follow Up (%) Withdrawn Consent (%) Cardiovascular Endpoint Adjudication by Blinded Central Committee UKPDS 33 (1998) 1 Open label NR 2.0% NR Two independent physicians assigned ICD-9 codes PROactive (2005) 2-4 Double blind 16.5% 0.04% 6.0% Primary and secondary endpoints, HF in retrospect ADOPT (2006) 5 Double blind 39.6% 5.4% 7.5% No. Retrospective adjudication of HF SAEs by 2 independent cardiologists DREAM (2006) 6 Double blind 23.2% 0.7% 1.3% Yes ACCORD (2008) 7 Open label 6.8% 0.49% 0% Yes ADVANCE (2008) 8 Open label 24.4% 0.15% NR Primary endpoint only, not HF BARI2D (2009) 9 Open label 1.8% 2.8% 2.4% Stroke and cause of death only, not HF RECORD (2009) 10 Open label 12% 2.8% 8.9% Yes VADT (2009) 11 Open label 14.5% 6.4% 6.1% Yes ORIGIN (2012) 12 Open label 19% 0.75% 0.2% Yes EXAMINE (2013) 13 Double blind 21.7% 0.5% NR Yes Look-AHEAD (2013) 15 Open label NR 3.7% NR Yes SAVOR-TIMI 53 (2013) 16 Double blind 19.6% 0.17% 2.4% Yes AleCardio (2014) 17 Double blind 27.3% 3.1% 3.2% Yes *Not mutually exclusive from lost to follow-up or withdrawn consent categorization. Abbreviations: ICD-9: international classification of diseases, 9th edition; HF: heart failure; NR: not reported; SAE: severe adverse events. 6
Appendix Table 3. Assessment of Publication Bias Outcome Egger s linear regression test P- value (1-sided) Heart failure 0.116 MACE 0.408 Expanded MACE 0.497 CV death 0.340 MI 0.118 Stroke 0.090 UA 0.384 Coronary revascularization 0.368 7
Appendix Table 4. Multivariate Meta-Regression Results Meta-regression Number of obs = 12 REML estimate of between-study variance tau2 = 0.01741 % residual variation due to heterogeneity I-squared_res = 59.69% Proportion of between-study variance explained Adj R-squared = 46.90% Joint test for all covariates Model F(6,5) = 1.59 With Knapp-Hartung modification Prob > F = 0.31 Variable Log RR P Age -0.0598 0.123 Duration of follow-up -0.0686 0.218 Duration of diabetes 0.0528 0.373 Proportion with CVD -0.0034 0.310 Mean absolute HbA1c achieved 0.5155 0.193 Weight gain 0.0420 0.322 8
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