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1 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 Jacob A Udell, Matthew A Cavender, Deepak L Bhatt, Saurav Chatterjee, Michael E Farkouh, Benjamin M Scirica Lancet Diabetes Endocrinol 2015; 3: Published Online March 17, S (15) See Comment page 310 Women s College Research Institute and Cardiovascular Division, Department of Medicine, Women s College Hospital (J A Udell MD) and Peter Munk Cardiac Centre, University Health Network (J A Udell, Prof M E Farkouh MD), Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada; Cardiovascular Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA (M A Cavender MD, Prof D L Bhatt MD, B M Scirica MD); and Division of Cardiology, St Luke s Roosevelt Hospital, Mount Sinai Health System, New York, NY, USA (S Chatterjee MD) Correspondence to: Dr Jacob A Udell, Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital and Women s College Hospital, Toronto, ON M5S 1B1, Canada jay.udell@utoronto.ca Summary Background Some glucose-lowering drugs or strategies adversely affect cardiovascular outcomes. We aimed to assess the extent to which glucose lowering by various drugs or strategies increases the risk of heart failure in patients with or at risk for type 2 diabetes, and to establish whether risk is associated with achieved differences in glycaemia or weight control. Methods We searched Ovid Medline, the Cochrane Library, and meeting abstracts up to Feb 20, 2015, for large randomised controlled trials of glucose-lowering drugs or strategies that assessed cardiovascular outcomes. The primary endpoint was incidence of heart failure. We derived pooled risk ratios (RRs) with random-effects models. Findings We included data from 14 trials, with mean duration 4 3 (2 3) years, comprising patients, of whom 3907 (4%) patients developed a heart failure event. Glucose-lowering drugs or strategies were associated with a 0 50% (SD 0 33) reduction in HbA 1c and a 1 7 kg (2 8) weight gain. Overall, glucose-lowering drugs or strategies increased the risk of heart failure compared with standard care (RR 1 14, 95% CI ; p=0 041). The magnitude of this effect varied dependent on the method of glucose lowering (p for interaction= ). Across drug classes, risk was highest with peroxisome proliferator-activated receptor agonists (RR 1 42, 95% CI ; six trials), intermediate with dipeptidyl peptidase-4 inhibitors (1 25, ; two trials), and neutral with insulin glargine (0 90, ; one trial). Target-based intensive glycaemic control strategies (RR 1 00, 95% CI ; four trials) and intensive weight loss (0 80, 95% CI ; one trial) were also not associated with development of heart failure. Metaregression analysis showed that for every 1 0 kg of weight gain associated with glucose-lowering drugs or strategies, there was a 7 1% (95% CI ) relative increase in the risk of heart failure compared with standard care (p=0 022). Interpretation Compared with standard care, glycaemic lowering by various drugs or strategies might increase the risk of heart failure, with the magnitude of risk dependent on the method of glucose lowering and, potentially, weight gain. Funding None. Introduction Heart failure is common in patients with type 2 diabetes and greatly affects health-care use, quality of life, and prognosis. 1 6 Epidemiological data have shown an association between glycaemia and incident heart failure events in patients with or at risk for type 2 diabetes, 5 12 similar to the association between glycaemia and atherothrombotic cardiovascular events in this patient population. 13 Many glucose-lowering drugs or strategies have been tested in randomised controlled trials of patients with type 2 diabetes, and others are presently being studied, to establish whether improved glycaemic control translates into reductions in atherothrombotic cardiovascular outcomes. However, some glucose-lowering drugs or strategies might have properties that result in beneficial or adverse haemodynamic effects, with a resultant effect on cardiovascular outcomes. 1 For instance, the drug class of agonists of the peroxisome proliferator-activated receptor (PPAR)-γ subtype (thiazolidinediones) cause fluid retention and weight gain, and a resultant increase in the risk of heart failure, despite a modest beneficial effect on atherothrombotic events. 14 Additionally, trials of other glucose-lowering drugs or strategies, such as dipeptidyl peptidase (DPP)-4 inhibitors (gliptins), have shown an increased risk of hospital admission for heart failure Because potential mediators of risk of heart failure in patients with type 2 diabetes are obesity and insulin resistance, 7,19 it is unclear to what extent the degree of glycaemic control, the method of glucose lowering, a difference in weight gain, or other study design characteristics affect the risk of heart failure in trials of glucose-lowering drugs or strategies. Furthermore, randomised controlled trials of glycaemic treatments are underpowered to detect differences in individual cardiovascular outcomes, including heart failure, 20 and previous meta-analyses omitted or only partly explored the risk of heart failure with glucose-lowering drugs or strategies Therefore, we systemically assessed data Vol 3 May 2015

2 from large randomised controlled trials of cardiovascular outcomes to define the risk of heart failure with glucoselowering drugs or strategies compared with standard care and to establish whether this risk is counterbalanced by any reduction in atherothrombotic events, with particular attention focused on effect modification by differential glycaemia or weight gain and other trial characteristics. Methods Search strategy and selection criteria We did a systematic review and meta-analysis to identify relevant published randomised controlled trials comparing experimental glucose-lowering drugs or modulation strategies with placebo or standard care according to the recommendations of the Cochrane Collaboration and the PRISMA guidelines. 28,29 We searched Ovid Medline and the Cochrane Library up to Feb 20, 2015, with MeSH and keyword search terms including diabetes mellitus, type 2, haemoglobin A1c, glycosylated, glycated, glucose, cardiovascular disease, heart failure, glycaemic control, glucose control, and intensive (appendix p 2). We restricted the search to randomised controlled trials of human adults (aged 19 years). We used no language restrictions. We screened titles and abstracts for eligibility and further searched and reviewed the supplemental appendices and reference lists of eligible papers for additional data and online cardiovascular conference abstracts between 2013 and 2014, and ClinicalTrials.gov, to ensure identification of relevant published and unpublished studies (appendix p 2). We included trials if they enrolled 1000 or more individuals with or at risk for type 2 diabetes (ie, prediabetes) and randomly assigned patients to investigational drugs or modulation strategies versus placebo or standard care that was exclusively focused on one risk factor (eg, glucose or weight) and resulted in an improvement in glycaemic control between treatment groups. We excluded trials that enrolled fewer than 1000 patients or patients with an acute cardiovascular event (eg, acute myocardial infarction, shock, or hospital admission for heart failure), or if they tested a multifactorial risk-factor intervention or non-glycaemic drug, or resulted in a mean difference of 0 1% or less in HbA 1c (or of 0 1 mmol/l in fasting plasma glucose if HbA 1c was not reported) between treatment groups. This design was intended to focus our analysis on large outcome trials with clinically relevant glycaemic differences between interventions that were powered to study composite cardiovascular endpoints to evaluate their atherothrombotic and heart failure effects over time in a stable population. Trials that compared three groups were reported as combined analyses comparing the experimental glucose-lowering drugs or strategies group with the two controls (metformin and glyburide). Outcomes The primary cardiovascular endpoint was incidence of heart failure. Secondary endpoints were major adverse cardiovascular events, which were included in preferential sequence if reported in the paper: the composite of cardiovascular death, myocardial infarction, or stroke; or cardiovascular death, myocardial infarction, or ischaemic stroke; or all-cause death, myocardial infarction, or stroke; or fatal and non-fatal myocardial infarction. Other secondary outcomes were an extended major adverse cardiovascular event endpoint, typically defined as a major adverse cardiovascular event plus hospital admission for unstable angina, coronary revascularisation, and, in some trials, heart failure; individual components of these composite endpoints besides heart failure; and allcause death (endpoint definitions for individual trials are listed in appendix p 5). Two investigators (JAU and MAC) independently extracted information about outcomes and trial characteristics from the published manuscripts and appendices; results were then compared and any disagreements were resolved by consensus. Statistical analysis Data for baseline characteristics were obtained with means (SDs), medians (IQRs), or rates from each study, and summary results were calculated weighted according to individual sample sizes. We used the originally reported hazard ratios (HRs) or risk ratios (RRs) from each study when available, or otherwise 3908 records identified 3899 through database searching 9 through other sources 3908 screened 26 randomised trials assessed for eligibility 14 randomised trials included in meta-analysis Figure 1: Study flow diagram 3882 excluded after screening titles and abstracts 12 excluded for not meeting inclusion criteria 3 enrolled <1000 patients 2 included patients with acute cardiovascular events 2 assessed multifactorial intervention 4 reported a 0 01% difference in fasting plasma glucose or HbA 1c 1 did not report cardiovascular outcomes See Online for appendix Vol 3 May

3 UK Prospective Diabetes Study 33 (1998) 35 Population N Intervention Control Age Outpatients with newly diagnosed type 2 diabetes receiving lifestyle management alone; excluded patients with myocardial infarction in the past year, present angina or heart failure, or polyvascular disease PROactive Outpatients with established (2005) 36 type 2 diabetes and atherothrombosis (coronary heart disease, stroke, or peripheral artery disease); excluded patients with recent acute coronary syndrome (<3 months), myocardial infarction (<6 months), stroke (<6 months), or coronary revascularisation (<6 months), or with symptomatic heart failure (NYHA class II) ADOPT Outpatients with recently (2006) 37 diagnosed type 2 diabetes receiving lifestyle management alone; excluded patients with unstable or severe angina, or known heart failure DREAM Outpatients with newly (2006) 38 diagnosed type 2 diabetes or prediabetes; excluded patients with previous cardiovascular disease (including heart failure) ACCORD Outpatients with established (2008) 39 type 2 diabetes and either cardiovascular disease or more than one risk factor ADVANCE Outpatients with established (2008) 40 type 2 diabetes and either atherothrombosis, microvascular disease, or multiple risk factors BARI2D Outpatients with established (2009) 41 type 2 diabetes and coronary heart disease candidates for revascularisation (angina or ischaemia); excluded patients with symptomatic heart failure (NYHA class III IV) or recent coronary revascularisation (<12 months) RECORD Outpatients with established (2009) 42 type 2 diabetes receiving metformin or sulfonylurea; excluded patients with recent admission to hospital for a cardiovascular event (<3 months) or known heart failure 3867 Intensive treatment with sulfonylurea or insulin (target fasting blood glucose <6 mmol/l) Standard care (diet; target fasting blood glucose <15 mmol/l) 53 3 (8 6) 5238 Pioglitazone Placebo 61 8 (7 7) 4351 Rosiglitazone (group 1) Metformin (group 2); glyburide (group 3) 56 9 (10 1) 5269 Rosiglitazone Placebo 54 7 (10 9) Intensive treatment (target HbA 1c <6%) Intensive treatment with gliclazide and other drugs as required (target HbA 1c 6%) 2368 Insulin sensitisation with oral treatment (metformin 75%, sulfonylurea 18%, thiazolidinedione 62%, insulin 29%) Standard care (HbA 1c %) Standard care (according to local guidelines) Insulin (metformin 10%, sulfonylurea 52%, thiazolidinedione 4%, insulin 61%) 4447 Rosiglitazone Metformin and sulfonylurea 62 2 (6 8) 66 (6) 62 4 (8 9) 58 4 (8 3) Followup 10 ( ) ( ) cardiovascular disease (%) 5238 (100%) 3608 (35%) 3590 (32%) 2368 (100%) 772 (17%) heart failure (%) duration of diabetes Change in fasting plasma glucose or HbA 1c (%)* NR NR NR 8 0 (4 13) NR (0 04) vs metformin; 0 42 (0 04) vs glyburide (5%) 156 (7%) 10 NR 7 9 (6 4) 21 (0 5%) 10 4 (8 7) 7 1 (4 9) (0 15) (0 2) Achieved fasting plasma glucose or HbA 1c (%) 7 0 ( ) ( ) (1 2) 7 5 Change in weight (kg)* (2 02) (0 28) vs metformin; (0 28) vs glyburide (8 6) (0 45) (Table continues on next page) Vol 3 May 2015

4 Population N Intervention Control Age Followup cardiovascular disease (%) heart failure (%) duration of diabetes Change in fasting plasma glucose or HbA 1c (%)* Achieved fasting plasma glucose or HbA 1c (%) Change in weight (kg)* (Continued from previous page) VADT (2009) 43 Outpatients with established type 2 diabetes; excluded patients with a recent cardiovascular event (<6 months), severe angina, or advanced heart failure 1791 Intensive therapy (treatment absolute difference in HbA 1c 1 5%) Standard care 60 4 (9 0) (40%) NR 11 5 (7 5) ORIGIN (2012) 44 Outpatients with newly diagnosed or established type 2 diabetes or prediabetes and atherothrombosis; excluded patients with known heart failure Insulin glargine Standard care 63 5 (7 9) 6 2 ( ) 7378 (59%) (6 0) ( ) EXAMINE (2013) 16,17 Outpatients with established type 2 diabetes and stabilised within days of an acute coronary syndrome (median 46 days); excluded patients with unstable cardiac disorders, including heart failure (NYHA class IV) 5380 Alogliptin Placebo 61 0 (10 0) 1 46 ( ) 5380 (100%) 1501 (28%) (0 04) 7 7 (1 1) (0 16) Look AHEAD (2013) 45 SAVOR TIMI 53 (2013) 15 Outpatients with established type 2 diabetes; excluded patients with a recent cardiovascular event (<3 months) or unstable cardiac disorders, including symptomatic heart failure (NYHA class III) Outpatients with newly diagnosed or established type 2 diabetes and either atherothrombosis or more than one risk factor; excluded patients with a recent or unstable cardiovascular event (<2 months) AleCardio (2014) 46 Outpatients with newly diagnosed or established type 2 diabetes and stabilised within 8 weeks of an acute coronary syndrome (mean 29 days); excluded patients with symptomatic heart failure (NYHA class II), or recent hospital admission for heart failure (<12 months) 5145 Intensive lifestyle intervention for weight loss (caloric restriction and exercise) Standard care 58 8 (6 9) Saxagliptin Placebo 65 1 (8 5) 7226 Aleglitazar Placebo 61 (10) Total (9 1) 9 6 ( ) 2 1 ( ) 2 0 ( ) 4 3 (2 3) 714 (14%) (79%) 7226 (100%) (57%) NR 5 0 (2 0 10) 2105 (13%) 759 (10%) 5039 (7%) 10 3 ( ) (4 9) 0 22 (0 03) 0 20 (0 01) 0 60 (0 03) 0 50 (0 33) (1 4) (0 92) 4 (1) 0 50 (0 15) (2 8) Data are mean (SD), median (IQR), or %, unless otherwise indicated. NR=not reported. NYHA=New York Heart Association. *Absolute achieved difference in fasting blood glucose, HbA 1c, or bodyweight between treatment groups at either 1 year or end of treatment, whichever was longer and reported. Absolute achieved HbA 1c in the glucose-lowering strategy group. Reported as baseline history of ischaemic heart disease. Range reported only. Table: Characteristics of included trials calculated RRs and 95% CIs from the reported number of events and patients per treatment group. Data from each trial were considered as per the intention-to-treat principle and we derived pooled RRs and 95% CIs with inverse-variance random-effects models. Trials that did not report a specific endpoint that could not be estimated from other outcomes were excluded from the pooled analysis of only that specific endpoint. We assessed heterogeneity for treatment effect across individual trials with use of the Cochran s Q statistic and the I² measure. 30 We further stratified results by the type of glucose-lowering drug or strategy tested, in view Vol 3 May

5 of the greater effect of some drugs on fluid retention, weight gain, and risk of heart failure, and to establish whether summary effects persisted when a drug class was removed from investigation in sensitivity analyses. A test for interaction with a model term representing effects stratified by treatment categories was calculated. 31 In further sensitivity analyses, we sequentially removed each study result from the pooled effect estimate, or incorporated smaller trials, or incorporated trials with interventions that resulted in a mean difference of 0 1% or less in HbA 1c. We used meta-regression to examine the association of treatment effects with various trial characteristics, including the difference in weight gain and glycaemic control between treatment groups, the absolute glycaemic control achieved in the experimental treatment group, the baseline duration of diabetes, the proportion of patients with established cardiovascular disease or heart failure, and trial duration. We assessed publication bias by visual inspection of funnel plots, with ascertainment for potential asymmetry of published results by Egger s linear regression test and Duval and Tweedie s trim and fill method Two-sided p values were calculated with p<0 05 considered significant for all tests. We did statistical analyses with Review Manager (version 5.3.4), Comprehensive Meta-Analysis (version 2.2), and STATA (version 11SE). Role of the funding source There was no funding source for this study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Results Figure 1 shows the study flowchart. We identified 26 eligible randomised controlled trials 15 17,35 59 of glucoselowering drugs or strategies in patients with or at risk for type 2 diabetes. 12 trials were excluded, leaving 14 trials that met inclusion criteria in the meta-analysis, comprising patients (figure 1) ,35 46 The table summarises individual trials and their characteristics. Six trials tested a PPAR agonist or PPAR-based strategy; two trials studied a DPP-4 inhibitor; one trial tested insulin glargine; four trials tested an intensive glycaemic target-based strategy; and one trial investigated an intensive weight-loss intervention. Six trials were unmasked open-label studies comparing interventions with routine standard care, five trials were double-blind placebo-controlled trials, two trials were unmasked trials with a specific active comparator, and one trial was a double-blind three-group active comparator trial. The double-blind trials tended to have higher rates of premature discontinuation of treatment than did the open-label studies, but overall, few patients were lost to follow-up or withdrew consent (appendix p 6). Definitions of cardiovascular endpoints were reported in each trial in accordance with standard diagnostic criteria, which allowed for comparisons across trials. Endpoints were available from all 14 trials for heart failure, major adverse cardiovascular events, expanded major adverse cardiovascular events, myocardial infarction, and stroke; from 12 trials for all-cause death alone; 15,16,35 37,39 41, trials for cardiovascular death alone; 15,16,35,36,38 40,42 46 seven trials for unstable angina; 15,36,38,43 46 and six trials for coronary revascularisation. 15,36,38,43,44,46 Outcome assessment was typically through clinical contact except for one trial that used administrative health-care service records. Outcome More glucose control Events Total Less glucose control Events Total Weight Heart failure risk ratio (95% CI) 1998 UK Prospective Diabetes Study PROactive ADOPT DREAM ACCORD ADVANCE BARI2D RECORD VADT ORIGIN EXAMINE 16, Look-AHEAD SAVOR-TIMI AleCardio % 9 5% 3 6% 0 7% 8 3% 9 3% 9 7% 4 8% 6 7% 9 8% 7 3% 9 5% 0 91 ( ) 1 43 ( ) 1 56 ( ) 7 03 ( ) 1 18 ( ) 0 95 ( ) 1 14 ( ) 2 10 ( ) 0 91 ( ) 0 90 ( ) 1 19 ( ) 0 80 ( ) 1 27 ( ) 1 22 ( ) Total % 1 14 ( ) Heterogeneity: Tau 2 =0 04; χ 2 =45 56, df=13; p<0 0001; I 2 =71% Test for overall effect: Z=2 04; p= Favours glucose-lowering Favours standard care Figure 2: Risk of heart failure events with glucose-lowering drugs or strategies versus standard care Determined with an inverse-variance random-effects model Vol 3 May 2015

6 adjudication for the primary endpoint was done in most trials (appendix p 6) (4%) patients developed a heart failure event and 9378 (10%) patients had a major adverse cardiovascular event. Compared with standard care, glucose-lowering drugs or strategies increased the risk of heart failure (figure 2). This association represented an absolute risk increase of 0 51%; however, the magnitude of this effect varied dependent on the method of glucose lowering (I²=71%; p for interaction= ; figure 3). Specifically, the risk was highest with PPAR agonists, intermediate with DPP-4 inhibitors, and neutral with insulin glargine (figure 3). Target-based intensive glycaemic control and intensive weight loss were also not associated with development of heart failure (figure 3). By contrast with findings for heart failure, glucoselowering drugs or strategies overall modestly lowered the risk of major adverse cardiovascular events (figure 4). This effect was driven by a reduction in myocardial infarction (p=0 017; figure 5). When we assessed an expanded major adverse cardiovascular events endpoint, the cardiovascular effect of glucose-lowering drugs or strategies was attenuated and no longer significant (p=0 10; figure 5). Consequently, glucose-lowering drugs or strategies had no significant effect on cardiovascular death, all-cause death, stroke, unstable angina, or coronary revascularisation (figure 5). Among atherothrombotic endpoints, these findings were consistent irrespective of strategy or drug class (all p for interactions 0 05; figure 5). In aggregate, the weighted mean difference in weight in patients randomly assigned to glucose-lowering drugs or strategies was +1 7 kg (SD 2 8), but weight change varied dependent on the method of glucose lowering. For instance, the mean difference in weight was +3 6 kg (SD 3 3) in trials of PPAR agonists, +2 2 kg (1 5) with intensive glycaemic control, +2 1 kg (SD not reported) PPAR agonists 2005 PROactive ADOPT DREAM BARI2D RECORD AleCardio 46 Subtotal Heterogeneity: Tau 2 =0 04; χ 2 =13 82, df=5; p=0 017; I 2 =64% Test for overall effect: Z=3 29; p= More glucose control Events Total Less glucose control Events Total Weight 9 5% 3 6% 0 7% 9 7% 4 8% 35 9% Heart failure risk ratio (95% CI) 1 43 ( ) 1 56 ( ) 7 03 ( ) 1 14 ( ) 2 10 ( ) 1 22 ( ) 1 42 ( ) DPP-4 inhibitors 2013 EXAMINE 16, SAVOR-TIMI Subtotal % 9 5% 16 8% 1 19 ( ) 1 27 ( ) 1 25 ( ) Heterogeneity: Tau 2 =0 00; χ 2 =0 15, df=1; p=0 70; I 2 =0% Test for overall effect: Z=2 94; p= Intensive control 1998 UK Prospective Diabetes Study ACCORD ADVANCE VADT 43 Subtotal % 8 3% 9 3% 6 7% 29 8% 0 91 ( ) 1 18 ( ) 0 95 ( ) 0 91 ( ) 1 00 ( ) Heterogeneity: Tau 2 =0 00; χ 2 =2 80, df=3; p=0 42; I 2 =0% Test for overall effect: Z=0 01; p=0 99 Insulin glargine 2012 ORIGIN 44 Subtotal % 9 8% 0 90 ( ) 0 90 ( ) Heterogeneity: not applicable Test for overall effect: Z=1 34; p=0 18 Weight loss 2013 Look-AHEAD 45 Subtotal ( ) 0 80 ( ) Heterogeneity: not applicable Test for overall effect: Z=1 67; p=0 10 Total Heterogeneity: Tau 2 =0 04; χ 2 =45 56, df=13; p<0 0001; I 2 =71% Test for overall effect: Z=2 04; p=0 041 Test for subgroup differences: χ 2 =21 85, df=4; p= , I 2 =81 7% % 1 14 ( ) Favours glucose-lowering Favours standard care Figure 3: Risk of heart failure events with glucose-lowering drugs or strategies versus standard care, stratified by strategy or drug class Determined with an inverse-variance random-effects model. PPAR=peroxisome proliferator-activated receptor. DPP=dipeptidyl peptidase. Vol 3 May

7 More glucose control Events Total Less glucose control Events Total Weight MACE risk ratio (95% CI) 1998 UK Prospective Diabetes Study PROactive ADOPT DREAM ACCORD ADVANCE BARI2D RECORD VADT ORIGIN EXAMINE 16, Look-AHEAD SAVOR-TIMI AleCardio % 7 0% 0 7% 0 6% 0 6% 8 0% 12 0% 3 5% 1 6% 22 2% 4 7% 6 1% 12 3% 0 84 ( ) 0 84 ( ) 1 31 ( ) 1 39 ( ) 0 90 ( ) 0 94 ( ) 0 91 ( ) 0 93 ( ) 0 82 ( ) 1 02 ( ) 0 96 ( ) 0 93 ( ) 1 00 ( ) 0 96 ( ) Total % 0 95 ( ) Heterogeneity: Tau 2 =0 00; χ 2 =13 48, df=13; p<0 0001; I 2 =4% Test for overall effect: Z=2 47; p= Favours glucose-lowering Favours standard care Figure 4: Risk of MACE with glucose-lowering drugs or strategies versus standard care Determined with an inverse-variance random-effects model. MACE=major adverse cardiovascular events. Major adverse cardiovascular events Expanded major adverse cardiovascular events All-cause death Cardiovascular death Myocardial infarction Stroke Heart failure Unstable angina Coronary revascularisation Favours glucose lowering Favours standard care Risk ratio (95% CI) p interaction 0 95 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0 07 Figure 5: Major adverse cardiovascular events and individual cardiovascular events with glucose-lowering drugs or strategies versus standard care Determined with an inverse-variance random-effects model. with insulin glargine, 0 36 kg (0 29) with DPP-4 inhibitors, and 4 0 kg (1 0) with intensive weight loss. Overall, risk of heart failure was associated with weight gain (p=0 022 for the meta-regression model), with each 1 0 kg relative increase in weight between treatments associated with a 7 1% (95% CI ) relative increase in the risk of heart failure (figure 6). Other trial characteristics associated with risk of heart failure with glucose-lowering drugs or strategies were mean duration of trial follow-up (a 13 7% [95% CI ] greater relative risk reduction for heart failure for each 1 additional year of follow-up; p<0 0001), history of cardiovascular disease (each 1% increase in the proportion of patients with previous cardiovascular disease associated with a 0 7% [95% CI ] relative increase in risk; p=0 0034), and the mean absolute HbA 1c achieved with glucose-lowering drugs or strategies (each 0 1% greater treatment-achieved HbA 1c associated with a 4 1% [95% CI ] relative increase in risk; p=0 0041). The mean difference in HbA 1c achieved (p=0 49), baseline duration of diabetes (p=0 061), baseline proportion of patients with heart failure (p=0 16), and baseline age (p=0 44) had no significant effect modification on heart failure risk between glucoselowering drugs or strategies and controls. By contrast, we recorded a 3 5% (95% CI ) greater reduction in relative risk for major adverse cardiovascular events with each 0 1% mean difference in HbA 1c achieved between glucose-lowering drugs or strategies and controls (p=0 027) and no association with weight gain (p=0 74). Visual inspection of funnel plots showed no evidence of publication bias affecting the results for heart failure or major adverse cardiovascular events (appendix pp 3, 4, 7). Results for the primary endpoint remained significant when we considered trials with interventions that resulted in a mean difference of 0 1% or less in HbA 1c (RR 1 13, 95% CI ; p=0 048), or those that enrolled fewer than 1000 individuals (1 14, ; p=0 038) with no additional evidence of publication bias (data not shown). However, with removal of the entire PPAR class of trials, the pooled effect of the other glucose-lowering drugs or strategies on the risk of heart failure was non-significant (RR 1 01, 95% CI ; p=0 86), although heterogeneity in risk across the remaining glucose-lowering drugs or strategies remained significant (p for interaction=0 0045) Vol 3 May 2015

8 as the RRs for the other drug classes were unchanged. In addition, removal of the entire PPAR class of trials resulted in weight gain no longer being a significant modifier of the risk for heart failure by glucose-lowering drugs or strategies (p=0 97), but a significant association remained between heart failure and trial duration (12 6% [95% CI ] greater relative risk reduction for heart failure for each 1 additional year of follow-up; p= ), baseline duration of diabetes (each 1 year increase in diabetes duration associated with a 9 4% [ ] relative increase in risk; p=0 0086), history of cardiovascular disease (each 1% increase in the proportion of patients with cardiovascular disease was associated with a 1 0% [ ] relative increase in risk; p=0 011), history of heart failure (each 1% increase in the proportion of patients with a history of heart failure associated with a 2 9% [ ] relative increase in risk; p=0 025), and the mean absolute HbA 1c achieved with glucose-lowering drugs or strategies (each 0 1% higher treatment achieved HbA 1c associated with a 3 4% [ %] relative increase in risk for heart failure; p=0 024). When considered in a multivariate metaregression model, no trial characteristic was an independent effect modifier of the risk of heart failure with glucose-lowering drugs or strategies (appendix p 8). Discussion This is the largest meta-analysis of the cardiovascular outcomes trials of glucose-lowering drugs or strategies tested in patients with or at risk for type 2 diabetes, and the first to focus on the risk of heart failure across various drugs or strategies ,60,61 In this meta-analysis of more than patients, there were four major findings. Overall, compared with standard care, treatment with glucose-lowering drugs or strategies resulted in a 14% relative increase in the risk of heart failure. There was significant heterogeneity in the magnitude of this effect, with the highest risk for PPAR agonists, intermediate risk with DPP-4 inhibitors, and a neutral risk with insulin glargine, target-based intensive glycaemic control, and intensive weight-loss strategies. Several other trial characteristics correlated with the risk of heart failure with glucose-lowering drugs or strategies, including weight gain, trial duration, and absolute glycaemic concentration achieved. The relative increase in the risk of heart failure seemed to outweigh a 5% relative risk reduction in major adverse cardiovascular events that was mainly driven by a reduction in myocardial infarction, although the absolute increase in risk of heart failure with glucose-lowering drugs or strategies was only 0 51%. The mechanism of action linking the increased risk of heart failure with glucose lowering remains controversial. 1,62 Our findings extend those of previous reports and confirm the substantial heterogeneity in risk of heart failure across drug classes and strategies of glucose lowering. With PPAR agonist-based interventions, the mechanism seems to be driven by an increase in Log risk ratio for heart failure RECORD Look-AHEAD AleCardio ADOPT SAVOR-TIMI EXAMINE 16, PROactive BARI2D ACCORD UK Prospective Diabetes Study ADVANCE ORIGIN VADT Change in weight (kg) 2006 DREAM 38 Figure 6: Relation between weight gain and heart failure Slope of the regression line is , which after exponentiation, translates into a 7 1% (95% CI ) relative greater risk for heart failure for every 1 0 kg increase in weight between glucose-lowering drugs or strategies versus standard care (p=0 022). weight, partly due to fluid retention, resulting in adverse haemodynamic consequences. 14 Our meta-regression analysis suggests that other glucose-lowering drugs or strategies might also be associated with an increased risk of heart failure despite a neutral or slight lowering effect on weight (eg, DPP-4 inhibitors). Besides weight gain, which did not show a consistent correlation with risk of heart failure when the PPAR-based trials were excluded, trial duration and baseline proportion of patients with established cardiovascular risk were strongly associated with heart failure. The association of baseline proportion of patients with established cardiovascular risk might be expected to indicate detection of potential harm in a secondary prevention diabetes population more sensitive to adverse haemodynamic effects or presence of nephropathy. 63 By contrast, the effect of trial duration was a surprising finding and supports calls for trials of cardiovascular outcomes in patients with type 2 diabetes to have extended follow-up to enable better assessment of the association between glucose lowering and heart failure. 1,20 Short trial duration might simply be a marker of a trial design that tested an intervention potentially associated with heart failure, or a marker of a potentially underpowered trial resulting in the chance for a falsepositive finding (type 1 error) when reporting a significantly harmful (or protective) result. Further results from ongoing trials can be compared with the data we analysed to confirm or refute these hypotheses. The mean difference in HbA 1c achieved between treatment strategies and duration of diabetes did not significantly affect the risk of heart failure with glucoselowering drugs or strategies. Combined with our finding of an association between the mean absolute HbA 1c achieved with glucose-lowering drugs or strategies and reduced risk of heart failure, these observations do not Vol 3 May

9 seem to support the myocardial defuelling hypothesis, which posits that any pharmacological reduction in blood glucose concentrations (and subsequently insulin concentrations) might be a mechanism of adverse haemodynamic effect in patients with type 2 diabetes with prolonged myocardial exposure to elevated concentrations of these substrates. 64,65 Our study has some limitations that are generally inherent to meta-analyses. We combined data from trials that varied in study design, intervention and controls, extent of glucose lowering, and definitions of cardiovascular endpoints including heart failure. However, we grouped interventions that were similar in the main mechanism of action or intended surrogate marker for modification, control therapies were contemporary standards of care with or without the use of a masked placebo, and endpoints involved common diagnoses, albeit of potentially varied severity and prognostic importance. Nevertheless, our approach might attenuate the summary effect of glucose lowering on major cardiovascular adverse events compared with previous, smaller, meta-analyses; 24 similarly, our results for the effect of glucose lowering on heart failure might also be an underestimate. Second, no individual patientlevel data were available. However, the primary results of this analysis would not be expected to substantially change with individual patient-level data, although such an approach might further delineate the independent effect of effect-modifying variables. Third, several studies had design limitations, including absence of masking and premature treatment discontinuation, that might restrict interpretation of the true effect of glucose lowering on heart failure. Nevertheless, masked adjudication of this outcome was done in all but two trials, and, when done in retrospect in one trial, confirmed the accuracy of investigator-reported serious events of heart failure. 66 Finally, despite the power of meta-regression to provide additional insight into causes of heterogeneity in meta-analysis, inferences from results must be considered hypothesis-generating. In summary, glucose lowering by various drugs or strategies might increase the risk of heart failure compared with standard care in patients with or at risk for type 2 diabetes. The magnitude of this risk seems to be driven by specific drug classes and correlated with other trial characteristics, including weight gain and trial duration. Conversely, glucose lowering by various drugs or strategies modestly decreased the risk of myocardial infarction. Clinicians should consider the trade-off between ischaemic and haemodynamic cardiovascular events when choosing between different drugs or strategies for lowering blood glucose. Contributors JAU did the literature search and data analysis, and drafted the figures. JAU and MAC did data collection. All authors analysed the data and interpreted the findings. JAU wrote the first draft of the manuscript and all authors provided critical revision of the manuscript for important intellectual content. Declaration of interests JAU reports that Brigham and Women s Hospital and the TIMI Study Group, with whom he was a trainee, received grant support from AstraZeneca and Bristol-Myers Squibb to undertake SAVOR-TIMI 53 before doing the present study; grants from the American College of Cardiology Foundation; and fees for consultancy from Cisbio Bioassays and Novartis outside the submitted work. MAC reports that Brigham and Women s Hospital and the TIMI Study Group received grant support from AstraZeneca and Bristol-Myers Squibb to conduct SAVOR-TIMI 53 prior to the conduct of the present study; and that he has been a consultant for AstraZeneca and Merck. DLB has received research grant support from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi-Aventis, and The Medicines Company; unfunded research for FlowCo, PLx Pharma, Takeda; has been an advisory board consultant for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; was a member of the board of directors of the Boston VA Research Institute, Society of Cardiovascular Patient Care; was Chair of the American Heart Association Get With The Guidelines Steering Committee; was a member of the data monitoring committee of the Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; and has received honoraria from American College of Cardiology (Senior Associate Editor, Clinical Trials and News), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor; Section Editor, Pharmacology), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today s Intervention), WebMD (CME steering committees), and Clinical Cardiology (Deputy Editor). MEF has received honoraria from the American College of Cardiology (Senior Associate Editor, Journal of the American College of Cardiology). BMS has received research grant support through the TIMI Study Group and Brigham and Women s Hospital from AstraZeneca and Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson and Johnson, Bayer Healthcare, Gilead, Eisai, Merck; and fees for consultancy from Arena, AstraZeneca, Boehringer-Ingelheim, Decision Resources, GlaxoSmithKline, GE Healthcare, Gilead, Lexicon, Merck, Eisai, St Jude s Medical, Forest Pharmaceuticals, Bristol-Myers Squibb, Boston Clinical Research Institute, Covance, University of Calgary, and Elsevier Practice Update Cardiology. SC declares no competing interests. 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