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WHITEPAPERThis Whitepaper is based on a Scientific Exchange meeting held on Saturday 14 December 2019 Meeting Attendees Chair: Professor Jonathan Shaw Endocrinologist, Deputy Director Baker Institute Other Participants: (alphabetical order) Professor Sof Andrikolopoulos (CEO, ADS) Professor John Atherton (cardiologist, QLD) A/Professor Ralph Audehm (GP, VIC) Dr Shane Nanayakkarra (cardiologist, VIC) Ms Heidi Roache (Partnerships, Baker Institute) Dr Anita Sharma (GP, QLD) Prof Sophia Zoungas (endocrinologist, Immediate Past President of ADS, VIC) Acknowledgment: AstraZeneca has provided an independent sponsorship to Baker Heart and Diabetes Institute for this report. BAKER HEART AND DIABETES INSTITUTEWHITEPAPER i Contents 1 Executive Summary 2 Benefits of SGLT2i 2 Public health imperative 3 Risks of SGLT2i 3 Barriers to SGLT2i use 4 SGLT2i Guidelines/Consensus Statement 4 1. Objective 5 2. Mechanism of Action of SGLT2 Inhibitors 6 3. Benefits of SGLT2 Inhibitors 7 Glucose lowering effects 7 Reduction in major adverse cardiovascular events (MACE) 7 Renoprotection 9 Benefits in heart failure participants with reduced ejection fraction 10 4. Absolute Mortality Benefit of SGLT2i 11 5. Risks Associated with SGLT2 Inhibition 12 Polyuria/nocturia 12 Genital infections 12 Volume depletion 12 Amputations and fractures 12 Diabetic ketoacidosis (DKA) 13 14 AEs in elderly patients 15 AEs in patients without diabetes 15 6. Barriers to SGLT2i Use 16 7. Guidelines or Consensus Statement: When and Who Should Initiate SGLT2i? 17 When to start SGLT2i? 17 Who should initiate SGLT2i treatment? 19 How long should SGLT2i treatment be continued? 19 Who should be involved with developing and endorsing consensus statement/guidelines? 19 References 20 WHITEPAPER: PRACTICALITIES OF USING SGLT2 INHIBITORS IN COMORBID DIABETES AND HEART DISEASE1This whitepaper has developed out of a round table discussion that was convened in December 2019 to explore the public health and clinical benefits and risks of sodium-glucose co-transporter-2 inhibitors (SGLT2i). The aim of this paper is to identify the major clinical issues surrounding the safe prescription of these agents. It is intended that this process will form the basis of more formal advice and guidance to be issued by relevant professional bodies, including the ADS, CSANZ and RACGP. The meeting focus was on cardiologists and general practitioners; however, the group stated that other groups including nephrologists, general physicians and endocrinologists would also benefit from further education on SGLT2i, particularly for patients with heart failure. Benefits of SGLT2i • SGLT2i improve glycaemic control in type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to increased glucuresis and natriuresis.[1] • Three large, randomised controlled trials (RCTs) (EMPA-REG,[4] CANVAS,[5] DECLARE[6]), as well as a recent meta- analysis by Zelniker et al 2019,[7] demonstrated SGLT2i have cardiovascular and reno-protective benefits in T2DM. • Additionally, a recent study of stable, well- treated heart failure patients with reduced ejection fraction (DAPA-HF) has demonstrated cardiovascular protection irrespective of the presence or absence of diabetes.[8] • In the systematic review and meta-analysis, Zelniker et al 2019[7] reported that SGLT2i use versus placebo resulted in a: – 14% reduction in major adverse cardiovascular events (MACE) in patients with previous atherosclerotic CV disease (HR: 0.86 [95% CI: 0.80-0.93]; p=0.0002). – 23% reduction in heart failiure (HF) hospitalisation/cardiovascular (CV) death (0.77 [0.71-0.84]; p<0.0001), with a similar benefit in patients with and without pre-existing atherosclerotic CV disease, and with and without a history of heart failure. – 45% reduction in the progression of renal disease (composite of renal worsening, end-stage renal disease or renal death) (HR: 0.55 [0.48-0.64]; p<0.0001) with a similar benefit in patients with atherosclerotic CVD and those with multiple CV risk factors. 2BAKER HEART AND DIABETES INSTITUTE• In the double-blind, placebo-controlled DAPA-HF trial in stable heart failure patients with reduced ejection fraction (EF≤40%),[8] dapagliflozin led to a: – 26% reduction in worsening heart failure or CV death (primary endpoint) (HR: 0.74; 95% CI: 0.65-0.85; p<0.001) (NNT: 21). This primary outcome benefit was present irrespective of the presence or absence of diabetes. – 30% relative risk reduction in worsening heart failure event (HR: 0.70 [0.59, 0.83]; p=0.00003). – Significant improvement in quality of life: The change in KCCQ total symptom score was 6.1 with dapagliflozin vs 3.3 for placebo; difference: 2.8 points [95% CI: 1.6, 4.0]; p<0.001]. Compared with placebo-treated patients, significantly more participants on dapagliflozin had an improvement in KCCQ score and significantly fewer participants on dapagliflozin had a deterioration in KCCQ score. • The exact mechanism(s) for the cardiovascular and renal protective effects of SGLT2i, however, remain unclear. • HbA1c is not a surrogate marker for SGLT2i reno-cardiovascular benefits. Public health imperative • The group agreed that there is a public health imperative to ensure SGLT2i are prescribed in appropriate patients, similar to initiation of other cardioprotective agents, such as ACE inhibitors, angiotensin receptor blockers (ARB), beta blockers and statins. To support this, it would be useful to not only quantify the absolute benefits of SGLT2i in terms of mortality, but also the impact of SGLT2i use on future dialysis and heart failure hospitalisation costs. • The absolute mortality benefits of SGLT2i use can be modelled on data taken from the National Diabetes Services Scheme (NDSS), which was published in The Dark Heart of Type 2 Diabetes Baker Institute Report 2017. [9] According to this data, a 30% reduction in mortality with SGLT2i use, as achieved in EMPA-REG study, would equate to 2,095 deaths prevented each year (assuming there was a 100% uptake rate). Even if the mortality benefit of SGLT2i use was only 10%, with a 50% uptake, there would still be 349 fewer deaths in one year. Risks of SGLT2i • Any potential benefits of SGLT2 inhibition should outweigh any potential risks. • Side-effects associated with SGLT2i include polyuria, genital infections, volume depletion in patients at risk of dehydration, and diabetic ketoacidosis (DKA).[4, 6] • The two side effects of SGLTS2i that cardiologists are most worried about are genital infections & DKA. • GPs are generally familiar with treating genital infections, and are accustomed to managing patients on SGLT2i, however, they may be concerned about DKA, particularly with broader SGLT2i use in the community. • Polyuria and genital infections are not usually dangerous, although they can be a nuisance for some patients. These AEs are usually mild to moderate and can be managed proactively by educating patients. Genital infections usually resolve with standard treatment, although recurrent genital infection may necessitate treatment discontinuation in a few patients. • Cardiologists may be more concerned about genital infections, as compared with GPs, as they are not used to treating these conditions. • For some patients, with a lower CV risk, the long-term benefits might not outweigh the inconvenience of frequent polyuria, nocturia or genital infections associated with SGLT2i. GLP-1 agonists may be a suitable alternative in some of these patients. WHITEPAPER: PRACTICALITIES OF USING SGLT2 INHIBITORS IN COMORBID DIABETES AND HEART DISEASE3• Because of their natriuretic effect, SGLT2i can cause volume depletion in patients taking loop diuretics or in other individuals who are at risk of dehydration (e.g. acute gastrointestinal illness). Fluid status in these patients should be checked before initiating a SGLT2i. Non- heart failure clinicians require more guidance with respect to dose adjustment of diuretics in heart failure patients. • DKA is a serious and potentially life- threatening condition caused by a “relative deficiency of insulin”. The American Diabetes Association defines DKA as the combination of blood pH<7.3, HCO 3 ≤18 mmol/L and elevated ketones. • A recent retrospective controlled cohort study across all public hospitals in Melbourne and Geelong confirmed that there is a small but significant increased absolute risk of DKA with SGLT2i [OR: 1.48; 95% CI: 1.02-2.15; p=0.037].[10] – Much of the excess risk of DKA occurred in people already admitted to hospital for other reasons, and most cases of DKA that developed during hospital admission occurred in the context of surgery and fasting. – In most cases of DKA, insulin was ceased in hospital when patients were fasting, and those involved in patient management may have been falsely reassured by blood glucose levels that were not particularly elevated, which could have contributed to the development of DKA in these patients. – This study highlights the need to educate medical staff about the risks of DKA in patients with T2DM on SGLT2i. However, it was also noteworthy that the absolute number of DKA cases was 3x higher in non-SGLT2i users, than in SGLT2i users. The most common probable precipitating factor for DKA in non-SGLT2i users was infection/acute illness. • SGLT2i should be withheld at least 2 days prior to surgery and not re-started until the patient is eating and drinking. • The working group determined further education about DKA was required and made a number of suggestions (please refer to Section 5, page 26 of this report). • It is important to put DKA into context, given the overall absolute risk of DKA with SGLT2i was small, and given there is also a background risk of DKA in people with diabetes not taking a SGLT2i. Barriers to SGLT2i use The major barriers preventing clinicians prescribing a SGLT2i in appropriate patients are: • side effects (e.g. polyuria, genital infections, DKA) • existing guidelines/indication/ reimbursement are based on glucose-lowering • cost SGLT2i Guidelines/ Consensus Statement • It was determined that there was a need to develop SGLT2i Guidelines or a Consensus Statement in collaboration with ADS and CSANZ, with contribution from General Practice via the RACGP. A nephrologist should also have input into the document and, possibly a geriatrician. • The Guidelines/Consensus Statement should clarify when to start SGLT2i. For example, should the SGLT2i be commenced during hospitalisation for HF or a CV event, at the first cardiology follow-up visit, by the endocrinologist or by the GP? • Please refer to sections 7 and 8 for a list of suggestions and proposed follow-up actions with respect to developing and implementing SGLT2i guidelines. 4BAKER HEART AND DIABETES INSTITUTEThe purpose of this whitepaper is to explore the benefits and risks of SGLT2i with the aim of ensuring the safe prescription of these agents in clinical practice. In particular, this whitepaper will explore: 1. safety issues of SGLT2i 2. clinical and public health benefits of intervention with SGLT2i. This whitepaper will focus on cardiologists and general practitioners; however, it was stated that endocrinologists would also benefit from further education on SGLT2i particularly for patients with heart failure. This whitepaper is hoped to act as a springboard for future collaboration with the Australian Diabetes Society (ADS) and the Cardiac Society of Australia and New Zealand (CSANZ) to develop a consensus/advisory statement for the safe use of SGLT2i. Objective WHITEPAPER: PRACTICALITIES OF USING SGLT2 INHIBITORS IN COMORBID DIABETES AND HEART DISEASE5Sodium-glucose co-transporters (SGLTs) are the specific mediators of renal glucose reabsorption, with 90% of this reabsorption being facilitated by the isoform termed SGLT2, and the remainder by SGLT1.[1] Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are known to improve glycaemic control in type 2 diabetes mellitus (T2DM) by reducing renal glucose reabsorption leading to urinary glucose excretion (glucuresis). Blocking the SGLT2 receptor also increases sodium excretion (i.e. promotes natriuresis).[1] Mechanism of Action of SGLT2 Inhibitors 6BAKER HEART AND DIABETES INSTITUTEIn addition to glucose lowering effects, three large, randomised controlled trials (RCTs), as well as a recent meta-analysis, demonstrate SGLT2i have cardiovascular and reno-protective benefits in patients with T2DM.[4-7] Additionally, a recent study of patients with heart failure with reduced ejection fraction (HFrEF) has demonstrated cardiovascular protection irrespective of the presence or absence of diabetes.[11] Glucose lowering effects The glucose lowering effects of SGLT2i have been established in multiple randomised, controlled trials in T2DM. The average reduction in HbA1c is approximately 1 percentage point, although glucose reduction varies according to the underlying baseline HbA1c and other factors. [12] The glucose-lowering effect of SGLT2i may be reduced in patients with an estimated GFR<60 mL/min/1.73 m 2 . It is important to note that the renal and cardiovascular benefits of SGLT2i are independent of the effect on HbA1c. Therefore, even if there is only minimal glucose lowering, large RCTs have established there are cardiovascular and renal benefits with a SGLT2i [13, 14]. Therefore, HbA1c is not a surrogate marker for SGLT2i reno-cardiovascular benefits, although it is an important marker of glucose-lowering. This may pose clinical challenges, as prescribers are generally accustomed to using an objective marker to track response to other medications. For example, the effect of an antihypertensive agent can be directly measured by blood pressure, and the effect of a cholesterol lowering agent can be measured by LDL-C or other lipid parameters. Therefore, without a biomarker to measure the renocardiovascular benefits of SGLT2i, there may be reluctance to prescribe the agents for non-glucose lowering effects. Moreover, adherence to medication may be poor if there is no measurable effect. Reduction in major adverse cardiovascular events (MACE) Three large, phase 3, randomised, placebo- controlled multinational trials have investigated the effect of SGLT2i on cardiovascular outcomes in people with T2DM: • EMPA-REG (empagliflozin)[4] • CANVAS (canagliflozin)[5] • DECLARE-TIMI 58 (dapagliflozin)[6] These studies have shown that SGLT2i led to a significant reduction in major cardiovascular events (i.e. myocardial infarction, stroke and CV death), and other CV outcomes such as heart failure/CV death in people with T2DM compared to placebo.[4-7] The populations in these outcome studies had different levels of baseline CV risk. Most participants in these studies had established atherosclerotic CVD; however some of the participants in CANVAS and DECLARE studies had multiple risk factors for CVD. All of the participants in EMPA-REG, 65.6% of participants in CANVAS and 40.6% of participants in DECLARE had pre-existing atherosclerotic CVD. Zelniker et al 2019 performed a systematic review and meta-analysis of the three SGLT2i CV outcomes trials (n=34,322) [7]. Compared to placebo-treated participants, the investigators reported that participants treated with a SGLT2i had a: • 14% reduction in MACE in participants with previous atherosclerotic CV disease (HR: 0.86 [95% CI: 0.80-0.93]; p=0.0002) (Figure 1). The hazard ratio for the reduction in MACE in participants without established atherosclerotic disease in this meta-analysis was 1.00 [95% CI: 0.87-1.16]; p=0.98).[7] The p value for subgroup differences was 0.0501. * Benefits of SGLT2 Inhibitors WHITEPAPER: PRACTICALITIES OF USING SGLT2 INHIBITORS IN COMORBID DIABETES AND HEART DISEASE7Next >