Dapagliflozin and cardiovascular outcomes in type 2

EARN 3 FREE CPD POINTS diabetes Leader in digital CPD for Southern African healthcare professionals Dapagliflozin and cardiovascular outcomes in type 2 diabetes Introduction People with type 2 diabetes (T2D) are at high risk for adverse cardiovascular (CV) outcomes and progressive decline in renal function. In comparison with the general population, they are 2 to 4 times more likely to be hospitalised or to die from CV causes, including atherosclerotic CV disease (ASCVD) and heart failure. 1-3 Approximately one third of patients with T2D who develop heart failure have no history of prior coronary heart disease, and while careful control of modifiable CV risk factors can ameliorate risk of death, myocardial infarction (MI) and stroke, the incidence of heart failure in T2D remains consistently higher than that of matched controls. 2,3 Therefore, prevention and treatment of these CV complications is fundamental to the management of T2D. Until recently, the primary requirement for trials of drug therapy for T2D has been to show glucose-lowering efficacy and safety. However, concerns over the CV safety of some more recently introduced antihyperglycaemic agents prompted the US Food and Drug Administration (FDA) to mandate that from 2008 all new drugs should also be tested for CV safety. 4 Furthermore, in the light of data from these CV outcomes trials, new 2018 recommendations for antihyperglycaemic therapy for adults with T2D include early incorporation of an agent proven to reduce major adverse CV events (MACE) and/or CV mortality. 5 Most CV outcomes trials have shown a neutral effect of antihyperglycaemic agents on CV events. However, well powered randomised controlled trials have demonstrated that the sodium-glucose co-transporter-2 (SGLT-2) inhibitors have favourable effects on CV and renal outcomes, which remain consistent across a broad range of patient subgroups. 4,6-8 The most recent of these studies is the Dapagliflozin Effect on Cardiovascular Events - Thrombolysis in Myocardial Infarction 58 (DECLARE- TIMI 58) trial, which was designed to evaluate the effects of dapagliflozin on CV and renal outcomes in a broad population of patients with T2D, including those with or without ASCVD. 8 The results of DECLARE-TIMI 58, which are summarised in this article, were presented at the 2018 Scientific Sessions of the American Heart Association in November. 9 Previous studies to evaluate CV benefits of SGLT-2 inhibitors This report was made possible by an unrestricted educational grant from Astrazeneca. The content of the report is independent of the sponsor. Empagliflozin The prospective, randomised EMPAREG trial (Empagliflozin, Cardiovascular outcomes, and mortality in Type 2 Diabetes) published in 2015 was the first to demonstrate that SGLT-2 inhibitors may be associated with significant and important CV benefits. It compared once daily empagliflozin to placebo in addition to standard diabetes care in 7 028 adults with T2D and established ASCVD (MI, december 2018 I 1

coronary artery disease, unstable angina, stroke or occlusive peripheral artery disease). 6 The median duration of treatment was 2.6 years and median observation time was 3.1 years. The primary outcome, a composite of death from CV causes, nonfatal MI (excluding silent MI) or nonfatal stroke, occurred in 10.5% of patients treated with empagliflozin compared with 12.1% in the placebo group (HR: 0.86, 95%CI: 0.74-0.99; P=0.04 for superiority). Rates of MI and stroke did not differ between groups, but in comparison with placebo, death from CV causes, hospitalisation for heart failure and all-cause mortality were reduced by 38%, 35% and 32% respectively among patients assigned to empagliflozin. Earn free CPD Points Join our CPD community at www.denovomedica.com and start to earn today! Canagliflozin Similar results were observed in the Canagliflozin Cardiovascular Assessment (CANVAS) program, which integrated data from two studies comparing canagliflozin to placebo in more than 10 000 patients with T2D and CV risk. 7 Approximately three quarters of the subjects had a history of atherosclerotic vascular disease (coronary, cerebrovascular or peripheral) and two thirds had a history of CVD. Over a mean followup period of 188 weeks, the primary Dapagliflozin A large prespecified meta-analysis of data from 21 dapagliflozin studies including 9 339 patients, 30% of whom had a history of CVD, indicated that overall dapagliflozin was associated with a 23% reduction in risk of MACE (composite of CVD death, MI and stroke). 10 In individuals with a history of CVD, the risk of MACE was reduced by 20%. Similar outcomes were observed in a large retrospective observational analysis (CVD-REAL Nordic) that evaluated data from more than 90 000 patients with T2D treated in real-world clinical practice with either an SGLT-2 inhibitor (n=22 830) or other glucose lowering drugs (n=68 490). The vast majority of patients on SGLT-2 inhibitors were treated with dapagliflozin (94%), whereas only 5% and 1% received empagliflozin or canagliflozin, respectively. The mean age at baseline was 61 years and prevalence of CVD was 25%. SGLT-2 inhibitors were associated with significantly decreased risks of CV mortality (relative risk reduction (RRR): 47%), MACE (RRR: 22%), hospitalisation for heart failure (RRR: 30%) and a decreased of severe hypoglycaemia (RRR: 24%). The risk reduction outcome comprising a composite of death from CV causes, nonfatal MI or nonfatal stroke was significantly reduced by 14% in the canagliflozin group. However, in this group there was also an increased risk of amputation, primarily at the level of the toe and metatarsal (6.3 vs 3.4 per 1 000 patient years; HR: 1.97; 95%CI: 1.41-2.75). Nevertheless, the results of CANVAS suggested that CV protection may be a class effect of the SGLT2 inhibitors. for CV mortality was similar in patients with or without a history of CVD, but the risk reduction for MACE was significantly greater among individuals with a history of CVD (HR: 0.7 for those with a history of CVD, HR: 0.90 for those without). 11 In an analysis of data from the same study, CV outcomes were compared for new users of dapagliflozin (n=10 227) versus new users of DPP-4 inhibitors (n=30 681), among whom 23% had established CVD at baseline. Treatment with dapagliflozin was associated with a significantly lower risk of MACE (21%), hospitalisation for heart failure (38%) and all-cause mortality (41%). 12 Because most of the patients in CVD-REAL Nordic were treated with dapagliflozin, the results of the study supported evidence for a possible class effect of SGLT-2 inhibitors on CV outcomes. However, in comparison with EMPAREG and CANVAS, this population was notable for a substantially lower CV risk profile at baseline, indicating that the beneficial effects may be extrapolated to patients with a much broader CV risk profile. 11 2 I december 2018

DECLARE-TIMI 58 Study design and baseline characteristics DECLARE-TIMI 58 was a randomised, double-blind, multinational, placebocontrolled phase 3 study in which 17 160 patients with T2D and established ASCVD (secondary prevention; n=6 974) or multiple CV risk factors (primary prevention; n=10 186) were randomised to dapagliflozin 10mg daily or placebo in addition to other treatments as usual. 8,9 Usual treatment was at the discretion of the treating physician. Inclusion criteria are listed in Table 1. After randomisation, the patients were followed up in person every 6 months and by telephone every 3 months in between clinic visits. The principle primary outcome of DECLARE-TIMI 58 was to demonstrate safety of treatment with dapagliflozin with respect to MACE. Additional prespecified primary and secondary endpoints relating to safety and efficacy are listed in Table 2. Table 1. DECLARE-TIMI 58 study inclusion criteria 8 Diagnosis of T2D 40 years of age HbA1c 6.5 and <12% CrCl 60ml/min/1.73m 2 AND Established ASCVD (secondary prevention) Ischaemic heart disease Cerebrovascular disease Peripheral artery disease OR Multiple CV risk factors (primary prevention) Men 55 years and women 60 years with at least one additional risk factor: Table 2. DECLARE-TIMI 58 study prespecified endpoints 8 Primary endpoints Safety (noninferiority versus placebo): 1. MACE: CV death, MI or ischaemic stroke Efficacy (superiority versus placebo): 1. MACE 2. Composite of CV death or hospitalisation for heart failure Secondary endpoints 1. Renal composite outcome: sustained decrease of 40% in egfr to <60ml/min/1.73m 2, new end-stage renal disease or death from renal or CV causes 2. Death from any cause 3. Sustained decrease of 40% in egfr to <60ml/min/1.73m 2, new end-stage renal disease or death from renal causes Dyslipidaemia Hypertension Current tobacco use CrCl: creatinine clearance; ASCVD: atherosclerotic cardiovascular disease Patients were followed up for a median of 4.2 years (interquartile range 3.9-4.4 years). An overview of baseline characteristics and medications is shown in Table 3. december 2018 I 3

Table 3. DECLARE-TIMI 58 study baseline characteristics (full cohort; N=17 160) 8 Age (mean) 64 years Female/male 37%/63% Body mass index (mean) 32kg/m 2 HbA1c (mean) 8.3% Duration of diabetes (median; interquartile range) 11 years; 6-16 years egfr (mean) 85.2ml/min/1.73m 2 egfr 60 to <90ml/min/1.73m 2 45% Secondary prevention cohort (established ASCVD) 41% Primary prevention cohort (multiple risk factors) 59% History of heart failure 10% Medications Metformin 82% Insulin 41% Sulfonylurea 43% DPP-4 inhibitor 17% GLP-1 receptor agonist 4% Antiplatelet agents 61% ACE inhibitor or ARB 81% Beta-blocker 53% Statin or ezetimibe 75% Diuretics 41% egfr: estimated glomerular filtration rate; DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; ACE: angiotensin converting enzyme; ARB: angiotensin receptor blocker Earn free CPD Points Join our CPD community at www.denovomedica.com and start to earn today! Outcomes Cardiovascular risk factors In comparison with placebo, HbA1c levels were lower in the dapagliflozin group throughout the trial (average leastsquares mean absolute difference between the groups: 0.42%; 95%CI: 0.40 to 0.45). During the course of the study, body weight declined from a mean baseline of 91kg in both groups with significantly greater weight loss in the dapagliflozin group. At 48 months follow up, mean body weight was 89kg in the placebo group and 87kg in the dapagliflozin group (mean difference 1.8kg (95%CI: 1.7-2.0kg)). Blood pressure was also reduced significantly more in the dapagliflozin group. At 48 months, mean systolic blood pressure (SBP) was 135mmHg in the placebo group and 132mmHg in the dapagliflozin group (mean difference 2.7mmHg; 95%CI: 2.4-3.0mmHg); and mean diastolic blood pressure (DBP) was 76mmHg in both groups, with a mean difference of 0.7mmHg (95%CI: 0.6-0.9mmHg) in favour of dapagliflozin. 4 I december 2018

Cardiovascular and renal outcomes Cardiovascular and renal outcomes are listed in Table 4. The rate of MACE was similar in the placebo and dapagliflozin groups, with dapagliflozin meeting the prespecified criteria for noninferiority (P<0.001). The incidence of composite outcome of CV death or hospitalisation for heart failure was significantly lower in the dapagliflozin group. This was primarily consequent to a lower rate of hospitalisation for heart failure in this group, whereas there was no significant difference in the rate of CV death. In subgroup analysis, the benefit of dapagliflozin in terms of rate of CV death or hospitalisation for heart failure was maintained across subgroups, including primary vs secondary prevention, history of heart failure (yes or no) and egfr ( 90, 60 to <90, and <60ml/min/1.73m 2 ). Table 4. DECLARE-TIMI 58 study cardiovascular and renal outcomes 8 Statistically significant differences are bold Endpoint Placebo Dapagliflozin Hazard ratio MACE Overall 8.8% 9.4% 0.93 (95%CI: 0.84-1.03) ASCVD subgroup 15.3% 13.9% 0.90 (95%CI: 0.79-1.02) Multiple risk factor subgroup 5.3% 5.2% 1.01 (95%CI: 0.86-1.20) CV death or hospitalisation Overall 5.8% 4.9% 0.83 (95%CI: 0.73-0.95) ASCVD subgroup 9.2% 7.8% 0.83 (95%CI: 0.71-0.98) Multiple risk factor subgroup 3.4% 2.8% 0.84 (95%CI: 0.67-1.04) History of heart failure 19.7% 16.6% 0.79 (95%CI: 0.63-0.99) No history of heart failure 4.2% 3.6% 0.84 (95%CI: 0.72-0.99) egfr 90ml/min/1.73m 2 3.9% 4.0% 0.96 (95%CI: 0.77-1.19) egfr 60 to <90ml/min/1.73m 2 6.5% 5.2% 0.79 (95%CI: 0.66-0.95) egfr <60ml/min/1.73m 2 12.3% 9.0% 0.78 (95%CI: 0.55-1.09) Hospitalisation for heart failure Overall 3.3% 2.5% 0.73 (95%CI: 0.61-0.88) ASCVD subgroup 9.3% 7.8% 0.83 (95%CI: 0.71-0.98) Multiple risk factor subgroup 3.4% 2.8% 0.84 (95%CI: 0.67-1.04) CV death 2.9% 2.9% 0.98 (95%CI: 0.82-1.17) 40% decrease in egfr to <60ml/min/1.73m 2, ESRD, or death from renal or CV causes 40% decrease in egfr to <60ml/min/1.73m 2, ESRD, or death from renal causes 5.6% 4.3% 0.76 (95%CI: 0.67-0.87) 2.8% 1.5% 0.53 (95%CI: 0.43-0.66) Death from any cause 6.6% 6.2% 0.93% (95%CI: 0.82-1.04) MACE: major adverse cardiovascular event; ASCVD: atherosclerotic cardiovascular disease; CV: cardiovascular; ESRD: end-stage renal disease december 2018 I 5

Safety of dapagliflozin Key safety findings are listed in Table 5. In general, individual adverse events were uncommon in both groups. Compared with placebo, dapagliflozin was associated with a significantly lower rate of treatment-emergent serious adverse events (SAE), major hypoglycaemia, acute renal injury and bladder cancer. The incidence of amputations and fractures, adverse events that had been flagged in previous studies with canagliflozin, was not significantly different in the dapagliflozin and placebo groups. Also, in contrast to findings in previous studies of SGLT-2 inhibitors, urinary tract infections and symptoms of volume depletion were not increased in the dapagliflozin group. In keeping with previous SGLT-2 inhibitor studies, adverse events that were more common with dapagliflozin included diabetic ketoacidosis and genital infections. Both were uncommon (27 and 76 patients respectively, out of 8 574 patients receiving dapagliflozin) and more than 80% of patients who experienced diabetic ketoacidosis were using insulin at baseline. Although adverse events leading to discontinuation were more common with dapagliflozin than with placebo, overall fewer patients in the dapagliflozin group discontinued the assigned trial regimen prematurely (21.1% in the dapagliflozin group vs 25.1% in the placebo group). Table 5. DECLARE-TIMI 58 study: Key safety events 8 Event Placebo (%) (n=8 569) Dapagliflozin (%) (n=8 574) P value Less common in the dapagliflozin group Treatment emergent SAE 36.2 34.1 <0.001 Major hypoglycaemia 1.0 0.7 0.02 Acute kidney injury 2.0 1.5 0.002 Bladder cancer 0.5 0.3 0.02 More common in the dapagliflozin group Adverse event leading to discontinuation 6.9% 8.1% 0.01 Diabetic ketoacidosis 0.1 0.3 0.02 Genital infection 0.1 0.9 <0.001 No significant difference between groups Amputation 1.3 1.4 0.53 Earn free CPD Points Join our CPD community at www.denovomedica.com and start to earn today! Fracture 5.1 5.3 0.56 Symptoms of volume depletion 2.4 2.5 0.99 Urinary tract infection 1.6 1.5 0.54 Hypersensitivity 0.4 0.4 0.57 SAE: serious adverse events 6 I december 2018

DECLARE-TIMI 58 in context DECLARE-TIMI 58 is a large study in a diverse group of patients with T2D at high risk for CV events. However, in contrast to EMPAREG and CANVAS, it included a large proportion of patients with CV risk factors, but without established ASCVD. 6-8 Compared with placebo, dapagliflozin was associated with a lower rate of CV death or hospitalisation for heart failure, which remained consistent across this broad range of patients regardless of history of heart failure or ASCVD. 8 The implications from DECLARE- TIMI 58 that the benefits of SGLT-2 inhibitors observed in patients with T2D and ASCVD, particularly in relation to progression to heart failure and possibly also progression of renal disease, extend also to patients without established ASCVD have been validated in a recent meta-analysis of these three large outcomes studies. 13 Analysis of the combined data showed that the effect of SGLT-2 inhibitors on MACE was modest and confined to individuals with a history of ASCVD. However, SGLT-2 inhibitors were associated with significant reductions in risk of hospitalisation for heart failure, composite of hospitalisation for heart failure and CV death, and composite of worsening of renal function, end-stage renal disease or renal death, and these effects were similarly robust in patients with ASCVD and those with multiple risk factors, but without ASCVD (Table 6). The benefits in terms of hospitalisation for heart failure and composite renal endpoint (renal worsening, ESRD, or renal death) were present regardless of baseline renal function, but the magnitude of benefit was dependent on baseline renal function. Rate of hospitalisation for heart failure was reduced by 40% among those with an egfr <60ml/min/1.73m², by 31% in those with egfr 60 to <90ml/ min/1.73m², and by 12% (not significant) in patients with egfr 90ml/min/1.73m² (P value for interaction = 0.007). In contrast, reduction of progression of renal disease was greatest among individuals with preserved renal function at baseline (RRR: 33%, 44% and 56%, respectively; P value for interaction = 0.026). Table 6. Meta-analysis of combined data from EMPAREG, CANVAS and DECLARE-TIMI 58 13 Outcome Hazard ratio (95%CI) Risk reduction vs placebo MACE: MI, stroke, CV death 0.89 (0.83-0.96) 11% ASCVD a 0.86 (0.80-0.93) c 14% Multiple risk factors (without ASCVD) b 1.00 (0.87-1.16) c NS Hospitalisation for heart failure a 0.61 (0.61-0.79) 31% Hospitalisation for heart failure and CV death 0.77 (0.71-0.84) 23% ASCVD a 0.76 (0.69-0.84) d 24% Multiple risk factors (without ASCVD) b 0.84 (0.69-1.01) d NS History of heart failure a 0.71 (0.61-0.84) e 29% No history of heart failure a 0.79 (0.71-0.88) e 21% Composite of renal worsening, ESRD, or renal death 0.55 (0.48-0.64) 45% ASCVD a 0.56 (0.47-0.67) f 44% Multiple risk factors (without ASCVD) b 0.54 (0.42-0.71) f 46% Fixed effects model; NS: not significant; ESRD: end-stage renal disease; a: includes data from EMPAREG, CANVAS and DECLARE-TIMI 58; b: includes data from CANVAS and DECLARE-TIMI 58; c: P for interaction 0.05; d: P for interaction 0.41; e: P for interaction 0.51; f: P for interaction 0.71 december 2018 I 7

Conclusions DECLARE-TIMI 58 adds to the growing evidence supporting the efficacy and safety of SGLT-2 inhibitors for treatment of T2D across a diverse patient population. Importantly, this class of drugs is associated with robust reductions in hospitalisation for heart failure and progression of renal disease, regardless of baseline atherosclerosis risk category or history of heart failure. 13 Consistent with previous studies of SGLT-2 inhibitors, DECLARE-TIMI 58 confirms that dapagliflozin has a favourable safety profile and significantly reduces CV risk factors important to patients with T2D, including HbA1c, blood pressure and weight gain. References Earn free CPD Points Are you a member of Southern Africa s leading digital Continuing Professional Development website earning FREE CPD points with access to best practice content? Only a few clicks and you can register to start earning today Visit www.denovomedica.com For all Southern African healthcare professionals 1. Rawshani A, Rawshani A, Franzén S, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017; 376: 407-418. 2. Rawshani A, Rawshani A, Franzén S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018; 379: 633-644. 3. Khan H, Anker SD, Januzzi JL, et al. Heart failure epidemiology in patients with diabetes mellitus without coronary artery disease. J Card Fail 2018. Published online. pii: S1071-9164(18)31120-5. DOI: 10.1016/j. cardfail.2018.10.015. 4. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol 2018. Published online. DOI: 10.1016/j.jacc.2018.06.040 5. American Diabetes Association. Summary of revisions: Standards of medical care. In Standards of medical care in diabetes 2018. Diabetes Care 2018; 41(Suppl 1): https://doi.org/10.2337/dc18-srev01 6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128. 7. Neal B, Mahaffey KW, de Zeeuw D, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657. 8. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2018. Published online 10 Nov 2018. DOI: 10.1056/NEJMoa1812389 9. Wiviott SD. Dapagliflozin Effect on Cardiovascular Events Thrombolysis in Myocardial Infarction 58 - DECLARE- TIMI 58. Presentation at American Heart Association (AHA) Scientific Sessions, 10 Nov 2018, Chicago, IL, USA. https://www.acc.org/latest-in-cardiology/clinicaltrials/2018/11/08/23/09/declare-timi-58 10. Sonesson C, Johansson PA, Johnsson E, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a metaanalysis. Cardiovasc Diabetol 2016; 15: 37. 11. Birkeland K, Jørgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diab Endocrinol 2017; 5(9): 709-717. 12. Persson F, Nyström T, Jørgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: A multinational observational study. Diab Obes Metab 2018; 20: 344-351. 13. Zelniker TA, Wiviott DSD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2018; (published online Nov 10.). DOI: 10.1016/S0140-6736(18)32590-X Find us at DeNovo Medica @denovomedica Disclaimer The views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities. Published by denovo Medica Reg: 2012/216456/07 70 Arlington Street, Everglen, Cape Town, 7550 Tel: (021) 976 0485 I info@denovomedica.com 8 I december 2018