key: cord-1038479-1b1hnmqo
authors: Savarese, Gianluigi; Schrage, Benedikt; Cosentino, Francesco; Lund, Lars H.; Rosano, Giuseppe M.C.; Seferovic, Petar; Butler, Javed
title: Non‐insulin antihyperglycaemic drugs and heart failure: an overview of current evidence from randomized controlled trials
date: 2020-09-10
journal: ESC Heart Fail
DOI: 10.1002/ehf2.12937
sha: f2fd033a53dc4c512e025f26780e62ee0761a76c
doc_id: 1038479
cord_uid: 1b1hnmqo

Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon‐like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium–glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF‐related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA‐HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM.

Heart failure (HF) and type II diabetes mellitus (T2DM) are highly prevalent and inflict a considerable financial burden on health care systems. 1,2 They often coexist, with 40% of patients hospitalized for HF also having diabetes and 12% of patients with diabetes suffering also from HF. 3, 4 Patients with concomitant HF and T2DM report worse prognosis as compared with those suffering from only one of these diseases. 5, 6 In 2008, the Food and Drug Administration and the European Medicines Agency revised the approval processes for glucose-lowering therapies, requiring cardiovascular (CV) outcome trials to be completed either before or after approval for any new antidiabetic medication. This decision followed the publication of a meta-analysis showing that rosiglitazone, although significantly lowering glycated haemoglobin, increased the risk of myocardial infarction, which led to questions regarding the use of glycaemic control as efficacy and registration outcome in randomized controlled trials (RCTs) evaluating the efficacy/safety of glucose-lowering drugs. 7 Although regulatory agencies focused on the risk of macrovascular events, rosiglitazone also significantly increased the risk of HF. Given the important interaction between T2DM and HF, worsening/hospitalization for HF has been used as an important secondary endpoint in all the recent RCTs focusing on T2DM treatments.

The aim of this review is to summarize and structure the current evidence on the interplay between glucose-lowering drugs and HF.

Non-insulin antihyperglycaemic medications inducing harm in heart failure: thiazolidinediones Thiazolidinediones (TZDs) effectively lower glucose levels by increasing insulin sensitivity in peripheral tissues. 8 In the PROACTIVE RCT, enrolling more than 5000 patients with T2DM and established macrovascular disease, pioglitazone vs. placebo reduced by 10% the risk of the primary outcome, which included any death, non-fatal myocardial infarction, stroke, acute coronary syndrome, coronary or leg arteries revascularization, or amputation above the ankle, 9 but also increased risk of HF hospitalization. 9 Similarly, in the RE-CORD trial, a 2.6-fold increased risk of HF requiring hospitalization or leading to death was observed in patients randomized to rosiglitazone on top of metformin or sulfonylurea monotherapy vs. a combination of metformin and sulfonylurea, whereas there was no difference in risk of CV death, myocardial infarction, and stroke. 10 Two meta-analyses confirmed these findings, suggesting a class effect for TZD on HF event risk, 11,12 which may be explained by renal sodium retention triggered by the peroxisome proliferator-activated receptor gamma activation by TZD. 13 Therefore, the use of TZD for treatment of T2DM in patients with HF is not recommended in the current European and American HF guidelines. 14, 15 Non-insulin antihyperglycaemic medications inducing potential harm in heart failure: inhibitors of dipeptidyl peptidase 4 and sulfonylureas Inhibitors of dipeptidyl peptidase 4

Inhibitors of dipeptidyl peptidase 4 (DPP4i) increase pre-prandial and post-prandial levels of GLP1, which promotes insulin secretion and suppresses glucagon secretion, leading to improved glycaemic control. 16 The SAVOR-TIMI 53 trial was the first large-scale RCT testing DPP4i vs. placebo on top of usual care in more than 16 000 patients with T2DM and either history or high risk of CV disease. 17 Although saxagliptin did not affect the primary major adverse cardiovascular event (MACE) endpoint, it significantly increased the risk of HF hospitalization by 27% as compared with placebo. 17 Notably, saxagliptin-associated increase in risk of HF hospitalization was greater in patients with history or at higher risk of HF (i.e. impaired renal function, or elevated baseline levels of N-terminal pro-B-type natriuretic peptides). 18 Although the underlying mechanisms for these findings are not clear, saxagliptin has been suggested to directly interact with myocytes and affect intracellular Ca 2+ levels, leading to impaired contractility. 19 In the EXAMINE trial, which tested alogliptin vs. placebo in patients with T2DM hospitalized for acute coronary syndrome, the MACE outcome was not met, and although the risk of HF was not significantly increased by the treatment, a higher number of HF events was observed in patients receiving alogliptin (3.1%) vs. placebo (2.9%). 20, 21 The finding of DPP4i increasing the risk of HF hospitalization could not be confirmed in other RCTs. Indeed, both the TECOS trial, 22 testing sitagliptin vs. placebo in T2DM patients with established CV disease, and the CARMELINA trial, 23 testing linagliptin vs. placebo in T2DM patients at high risk of CV and renal diseases, showed no effect of DPP4i on HF-related endpoints nor on the primary MACE outcome. 24, 25 Finally, in the VIVIDD trial, enrolling 254 patients with T2DM and HF with reduced ejection fraction (HFrEF) (<40%), vildagliptin (vs. placebo) did not affect ejection fraction (EF) but increased left ventricular volumes. 26 The study also showed that vildagliptin increased, albeit not significantly, CV mortality. The CAROLINA trial, which randomized 6033 T2DM patients with or at increased risk of CV disease to linagliptin vs. the sulfonylurea glimepiride on top of standard care, showed no increased risk of MACE and of HF-related outcomes with linagliptin vs. glimepiride over a median follow-up of more than 6 years. 27 An increased risk of HF was thus observed only in the SAVOR-TIMI 53 with concordant signals in EXAMINE and VIVVID. However, a possible increase in occurrence of HF hospitalizations cannot be completely ruled out in the studies with DPP4i reporting a null effect given that HF hospitalizations had not been prospectively assessed and adjudicated. The Food and Drug Administration expanded the warning regarding cautious use in HF patients to the whole DPP4i class and consistently amended product labels.

Sulfonylureas facilitate insulin release and hereby lower blood glucose levels, but clinical use of these drugs is limited by side effects such as weight gain and a high risk of hypoglycaemia. 28 Although CV safety of sulfonylureas has been debated for many years, the evidence on this topic is mostly based on observational data. 28 In a meta-analysis of Antihyperglycemic drugs in HF observational studies, as well as in a propensity score matched analysis of the National Veterans Health Administration databases, use of sulfonylureas was associated with higher risk of HF as compared with metformin. 29, 30 However, in the UKPDS 33 trial, which randomized 3867 patients with T2DM to intensive vs. conventional blood glucose control with sulfonylureas or metformin vs. diet, no study treatment increased risk of CV events, including HF. 31 In the ADOPT trial, randomizing 4360 patients with T2DM to rosiglitazone, glyburide, or metformin, glyburide was associated with a lower risk of CV events (including HF) than was rosiglitazone, and the risk associated with metformin was similar to that with rosiglitazone. 32 Finally, in a recent retrospective cohort study of 132 737 patients with T2DM, starting sulfonylureas on top of metformin or no previous antidiabetic treatment was associated with a higher risk of CV events, and in particular of HF, compared with initiating DPP4i. 33 Conversely, in the CAROLINA trial, the risk of CV events, including also HF, did not differ in patients receiving glimepiride vs. DPP4i linagliptin. 27 Overall, the available data regarding the risk of HF with sulfonylureas are conflicting, and these agents might be or not be harmful in patients with or at risk of HF. Therefore, other antihyperglycaemic treatments with proven safety/efficacy profile should be preferred to sulfonylureas in T2DM patients with or at high risk of HF.

Non-insulin antihyperglycaemic medications with potential neutral effect in heart failure: glucagon-like peptide 1 receptor agonists Glucagon-like peptide 1 (GLP1) increases insulin secretion and downregulates glucagon in response to food intake, improving glycaemic control. 34 GLP1 receptor antagonists (GLP1-RAs) enhance this effect and reduce appetite, inducing also weight loss. 34 Experimental studies in animal models show that lack of GLP-1R results in impaired left ventricular contractility and decreased resting heart rate. 35 Notably, GLP-1 infusion increases left ventricular contractility, stroke volume, and cardiac output in animal models of induced dilated cardiomyopathy. 36 All these data, together with the evidence of a role for GLP-1 on post-ischaemia recovery and myocardial viability, have suggested a potential benefit for GLP-1RA in patients with T2DM and concomitant HF. 37, 38 Several CV outcome trials have evaluated efficacy and safety of GLP1-RA. The ELIXA trial randomized 6068 patients with T2DM and a recent acute coronary syndrome to lixisenatide vs. placebo. Lixisenatide did not reduce the primary outcome of the trial (composite of CV death, myocardial infarction, stroke, or hospitalization for unstable angina) or any of the secondary endpoints, including also HF hospitalization. 39 Similarly, the EXSCEL trial, randomizing 14 752 patients with T2DM with or without pre-existing CV disease, showed that exenatide was not superior to placebo in terms of MACE risk reduction. 40 Although exenatide reduced the composite endpoint of all-cause mortality and hospitalization for HF in the overall cohort, this benefit was attenuated in patients with prevalent HF at baseline. 41 In the LEADER, SUSTAIN-6, and HARMONY OUTCOMES trials, the GLP1-RA liraglutide, semaglutide, and albiglutide, respectively, reduced the MACE endpoint as compared with placebo, but, once again, not the risk of HF hospitalization. 42-44 Finally, PIONEER-6, randomizing 3183 subjects at high CV risk, showed semaglutide being non-inferior to placebo for risk of MACE and HF hospitalization, but decreasing the risk of CV death by 51% and the risk of all-cause death by 49%. 45 Interestingly, in a recent meta-analysis of all major CV outcome trial on GLP1-RA, these drugs were reported to slightly reduce the risk of HF hospitalization. 46 Two phase II RCTs have focused on investigating liraglutide vs. placebo in HF patients with or without concomitant T2DM. The FIGHT trial randomized 300 patients hospitalized for acute HFrEF (<40%). 47 The primary outcome was a global rank score in which all patients, regardless of treatment assignment, were ranked across three hierarchical tiers: time to death, time to HF rehospitalization, and time-averaged proportional change in N-terminal pro-B-type natriuretic peptide level from baseline to 180 days. 47 The LIVE trial randomized 241 patients with clinically stable HFrEF (<45%) and on optimal HF treatment with or without T2DM. 48 The primary endpoint was change in EF from randomization to end of follow-up. 48 Neither FIGHT nor LIVE met their primary outcome. 47, 48 Notably, in LIVE, a significant increase in heart rate as well as in the occurrence of serious cardiac and HF-related events was observed in the liraglutide vs. the placebo arm. 48 Albeit the exploratory nature and the small number of patients and events, these results have questioned the use of GLP1-RA in patients with HF. Finally, the REWIND trial, which has randomized 9901 T2DM patients with or at high risk of CV disease to dulaglutide vs. placebo, also showed a reduction in risk of the primary MACE outcome but no differences for HF hospitalization. 49 Non-insulin antihyperglycaemic medications with potential benefit in heart failure: metformin Besides classical glucose-lowering mechanisms, that is, reduction of hepatic gluconeogenesis and increasing peripheral insulin sensitivity, metformin has been recently suggested to act on the intestine by increasing GLP-1 secretion and possibly altering the microbiome. 50 Metformin has been the cornerstone of T2DM therapy for decades, which has led to a deep clinical experience with its use. The cardioprotective role of metformin has emerged in the UKPDS trials, with the UKPDS 34 showing a reduction in risk of diabetes-related endpoints and mortality in overweight patients with newly diagnosed T2DM receiving metformin vs. diet. 51 In the UKPDS 80 trial, metformin was shown to reduce the risk of any diabetes-related endpoint, including also HF, and of myocardial infarction and mortality compared with diet over a follow-up of 10 years. 52 However, a recent meta-analysis of RCTs could not report any reduction in risk of HF linked with use of metformin vs. placebo or other treatments. 53 Metformin may be beneficial in patients with HF by enhancing glucose uptake in insulin-resistant cardiomyocytes and attenuating remodelling as suggested by experimental studies 54,55 and by improving myocardial efficiency by reducing myocardial oxygen consumption. 56 Importantly, metformin use was initially limited to non-HF T2DM patients due to concerns regarding a potentially increased risk of lactic acidosis, 57 which has been proven to be very low in clinical practice (<10 cases per 100 000 patient-years). 58 Similarly, the glomerular filtration rate label criterion for metformin has been lowered from ≥60 to ≥30 mL/min in the past years, as concerns regarding its safety in patients with moderately reduced kidney function could not be confirmed. 59 The European Society of Cardiology (ESC) guidelines on HF and the recent ESC guidelines on diabetes recommend metformin as a treatment option for T2DM patients with HF (class IIa; level C), 14,28 whereas the American Heart Association/American College of Cardiology guidelines are more cautious. 60 Notably, current evidence on metformin is mainly based on extensive clinical experience, observational studies and smaller RCTs assessing primarily glycaemic control, because metformin has not been tested in CV outcome trials. 61 In a nested case-control study enrolling around 3500 patients with both HF and T2DM, metformin use was significantly associated with improved survival, as compared with patients not exposed to any antidiabetic drug. 62 Similarly, in a propensity score matched analysis of around 6000 patients with T2DM and concomitant HF, treatment with metformin vs. other antidiabetic treatments was associated with a 24% improved survival. 63 In a propensity score matched analysis of around 130 000 patients with T2DM, those receiving metformin had 32% lower risk of being hospitalized or dying for HF as compared with patients treated with a sulfonylurea. 30 However, metformin did not improve exercise capacity in a randomized trial of 62 HFrEF patients comparing metformin vs. placebo and had no effect on risk of HF in a meta-analysis of RCTs. 61, 64 Non-insulin antihyperglycaemic medications with benefit in heart failure: sodium-glucose cotransporter protein 2 inhibitors Sodium-glucose cotransporter protein 2 inhibitors (SGLT2i) block the sodium-glucose cotransporter protein 2 in the proximal convoluted tube of the kidney. They increase urinary glucose excretion (i.e. glycosuria) but do not increase the risk of hypoglycaemia (unless paired with insulin or sulfonylurea), as the extent of glucose lowering depends on starting glucose (and is therefore smaller in patients with low glucose levels). The glycosuria and concomitant natriuresis lead to a decrease in extracellular volume, 65 which may promote a reduction in vascular wall stress, less congestion, and improved cardiac function. 66 By preventing coupled glucose and sodium reabsorption in the proximal tubule, sodium delivery to the macula densa increases, which leads through tubulo-glomerular feedback to afferent arteriole adenosine-induced vasoconstriction and therefore attenuation of chronic hyperfiltration responsible for nephron loss. 65 Interestingly, it has been suggested that while conventional diuretics reduce intravascular volume and thus cause maladaptive neurohormonal activation, SGLT2i may be associated with greater vascular refill and greater reduction of interstitial fluid. 67 SGLT2i have also metabolic effects on the heart. By increasing glucagon levels, they may exert a positive inotropic and chronotropic effect. 68 Additionally, by increasing hydroxybutyrate levels, they may foster a shift in myocardial fuel supply from fatty acids and glucose to the more energy-efficient ketones in the diabetic heart. 69 Finally, SGLT2i foster the inhibition of the sodium-hydrogen exchanger in the heart, which has been shown to minimize cardiomyocyte injury and attenuate the development of cardiac hypertrophy, remodelling, systolic dysfunction, and fibrosis. 70 Both haemodynamic, metabolic, and renal effects induced by SGLT2i may be particularly beneficial in patients with HF. 70 The first landmark trial to evaluate the efficacy and safety of SGLT2i in T2DM patients was the EMPA-REG OUTCOME. 71 This RCT allocated 7020 individuals with T2DM and established CV disease to receive empagliflozin vs. placebo. Over a median follow-up of 3.1 years, empagliflozin reduced the risk of the primary outcome (i.e. composite of CV death, myocardial infarction, or stroke) by 14%, CV death by 38%, all-cause mortality by 32%, and notably, risk of HF hospitalization by 35%. 71 These benefits were consistent in patients with and without HF at baseline, as well as in patients at different risk of HF outcomes. 72 A post hoc analysis of the EMPA-REG OUTCOME trial showed that empagliflozin may reduce the risk of HF hospitalization, CV, and any death following a first hospitalization for HF, providing a rationale for studying SGLT2i specifically in the post-acute HF window. 73 Antihyperglycemic drugs in HF More recently, the CANVAS trial, 74 which investigated canagliflozin vs. placebo in T2DM patients with established or high risk of CV disease, canagliflozin significantly reduced the primary MACE endpoint by 24% but not its individual components. 74 Like empagliflozin, 72 canagliflozin significantly reduced the risk of HF hospitalization by 33%. 74 Notably, the observed absolute, but not relative, risk reductions of CV death or HF hospitalization and of HF hospitalization alone were greater in patients with vs. without a history of HF. 75 Additionally, the CREDENCE trial, which was planned to randomize 6000 patients with T2DM and chronic kidney disease to either canagliflozin or placebo, was stopped earlier as a planned interim analysis showed a 30% lower risk of the primary endpoint (end-stage renal disease/doubling of serum creatinine/death from renal or CV cause) in the intervention arm. 76 Interestingly, canagliflozin was also shown to reduce the risk of HF hospitalization by 39%. 76 The EMPA-KIDNEY and the DAPA-CKD trials, which evaluate the effect of empagliflozin/dapagliflozin in patients with chronic kidney disease, are currently ongoing and will provide further evidence. 77, 78 Of note, DAPA-CKD has recently been stopped for efficacy, per a press release issued by the manufacturer. 79 Recently, the results of the third landmark trial evaluating efficacy/safety of SGLT2i were published. The DECLARE TIMI 58 trial randomized 17 160 T2DM patients with history or at high risk of CV disease to dapagliflozin or placebo. Dapagliflozin did not significantly reduce the risk of MACE, but led to a 17% significant reduction of risk of CV death or HF hospitalization, which was mainly driven by a reduction of HF hospitalization. 80 Notably, in a post hoc analysis, dapagliflozin reduced the risk of HF hospitalization in patients with HF, regardless of EF, as well in those without HF, but reduced the risk of CV and all-cause death only in patients with HFrEF. 81 One more trial on the SGLT2i ertugliflozin vs. placebo, the VERTIS-CV, is currently ongoing and enrolling patients with T2DM and established CV disease. It is expected to enrol 8000 patients, and results are expected in 2020. HF hospitalization is one of the secondary endpoints considered in this trial. 82 The consistent finding of SGLT2i reducing HF-related hospitalizations in patients with/without established HF supports a potential class effect for these drugs on HF events. These trial findings, together with an emerging understanding of mechanisms of action of this pharmacological class, have led to the hypothesis whether SGLT2i may be beneficial in terms of mortality/morbidity reduction also in HF patients without T2DM, who were not enrolled in the above-mentioned trials. Several RCTs are testing this hypothesis, that is, SGLT2i as an HF treatment, irrespective of coprevalent T2DM. The DAPA-HF, randomizing 4744 patients with symptomatic HFrEF (≤40%), with and without T2DM, to dapagliflozin vs. placebo, was the first and so far only RCT to report. 83 Over a median follow-up of 18.2 months, dapagliflozin reduced the primary composite outcome of CV death or worsening HF by 26%. 83 This effect was consistent for all the individual components of the composite endpoint as well as across several pre-specified subgroups, including patients with and without T2DM at baseline. 83 Notably, the benefit in terms of hard outcomes was paralleled by an improvement in symptoms, physical function, and quality of life. 84 Furthermore, the trial did not raise any relevant drug-related safety concern regardless of age, as there was no higher incidence of volume depletion or serious adverse renal events in the treatment group. 84, 85 Later in the DEFINE-HF trial, randomizing 263 patients with HF and EF ≤ 40%, NYHA classes II-III, elevated natriuretic peptides, with and without T2DM, to dapagliflozin 10 mg daily vs. placebo for 12 weeks, patients receiving dapagliflozin were more likely to experience clinically meaningful improvements in a dual primary endpoint of HF-related health status or ≥20% decrease in natriuretic peptide levels, although there was no significant difference in the mean natriuretic peptide levels between study groups. 86 More recently, the EMPERIAL-Reduced (EF ≤ 40%) and EMPERIAL-Preserved (EF > 40%) trials, both randomizing 300 patients with chronic HF to empagliflozin vs. placebo, could not show an effect on exercise capacity (change in 6-min walk distance from baseline to a 12-week follow-up). 87 In an RCT enrolling 80 acute HF patients with and without T2DM, empagliflozin 10 mg/day vs. placebo for 30 days did not significantly improve dyspnoea, diuretic response, natriuretic peptide levels, and length of hospital stay. 88 Upcoming evidence on sodium-glucose cotransporter protein 2 inhibitors Several phase III RCTs on SGLT2i are currently ongoing in HF with both reduced and preserved EF. The DELIVER trial aims to test the efficacy of dapagliflozin in terms of reduction of CV death or HF hospitalization/urgent visit in 4700 patients with symptomatic HF with EF > 40% regardless of T2DM status. 89 The EMPEROR-Preserved trial enrolling patients with HF with EF > 40% and the EMPEROR-Reduced in HF with EF ≤ 40% will randomize 5750 and 3600 symptomatic HF patients regardless of T2DM status, respectively, to empagliflozin vs. placebo. 90, 91 Both trials use a different primary endpoint as compared with DAPA-HF, that is, composite of CV death and HF hospitalization, excluding urgent visits not leading to hospitalization. Furthermore, the EMPEROR-Reduced trial aims to enrol patients with more severe HF as compared with DAPA-HF, as explained by the higher N-terminal pro-B-type natriuretic peptide cut-off for patient inclusion. 90 Finally, the SOLOIST-WHF trial was estimated to randomize 4000 patients with haemodynamically stable HF, regardless of EF, and T2DM, following a hospital admission for worsening HF, to sotagliflozin vs. placebo, 92 but was closed out early due to funding and COVID-19 ▪12 weeks, 1:1 randomized, placebo-controlled trial 263 patients with symptomatic HFrEF and elevated natriuretic peptides Improvement in HF related health status or natriuretic peptides, but no reduction of mean natriuretic peptide levels ACS, acute coronary syndrome; CV, cardiovascular; HF, heart failure; HFpEF: heart failure with preserved ejection fraction; HFrEF: heart failure with reduced ejection fraction; MI, myocardial infarction; T2DM, type 2 diabetes mellitus. In HF patients with an established, non-TZD/saxagliptin based antihyperglycaemic therapy and with good glycaemic control, current ESC guidelines recommend to add a SGLT2i-based regimen to counteract worsening HF. 28 Dapagliflozin is the only SGLT2i, which, up to date, has been shown to be effective in HF without T2DM. Use of SGLT2i as HF treatment, that is, regardless of T2DM status, is not considered yet in either American or European guidelines and does not yet have a regulatory label. Ongoing trials will add to the evidence in HFrEF and will show whether the effect shown by dapagliflozin in HFrEF will also hold true in HFpEF. At present, it is possible to advocate a class effect for SGLT2i for the prevention of HF in patients with T2DM while only dapagliflozin should be considered for the treatment of HF regardless of the presence of T2DM.

SGLT2i are well tolerated, and in general, side effects of this drug class are genital and urinary tract infections. However, increased urinary tract infections were not demonstrated with dapagliflozin in DAPA-HF. SGLT2i can also cause polyuria with volume depletion. 94 Whether the combination of SGLT2i and sacubitril/valsartan might lead to excessive diuresis/hypotension represents a current gap in the evidence according to the guidelines and deserves further investigation. 28 The combination of dapagliflozin and sacubitril/valsartan was well tolerated in DAPA-HF and no increased risk of hypotension leading to discontinuation of either drug was observed, although the subsample of subjects receiving both medications was relatively small. Additionally, in a recent post hoc analysis of the DAPA-HF trial, the benefit of dapagliflozin was consistent regardless of background HF therapy, including sacubitril/valsartan. 96 Concomitant diuretic therapy, however, should be carefully monitored and, if needed, reduced upon initiation of SGLT2i or initiation or uptitration of sacubitril/valsartan. These issues might be of particular importance in patients with pre-existing chronic kidney disease and in older patients, who might be more sensitive to shifts in volume status. Finally, more severe complications such as diabetic keto acidosis or Fournier's gangrene (the latter only seen with canagliflozin) are rare but should be kept in mind. 94 Additionally, diabetic keto acidosis was not increased by dapagliflozin in diabetic and non-diabetic HF patients in DAPA-HF (Tables 1 and 2 ).

The interplay and mutual risk increase in T2DM and HF highlight the need to identify antihyperglycaemic agents able to prevent HF in T2DM patients and to improve mortality/morbidity in those with T2DM and established HF. Current evidence supports the use of SGLT2i as primary treatment for T2DM in patients with and at high risk of HF. At present, dapagliflozin has shown benefit for the treatment of diabetic and non-diabetic patients with HFrEF. Should the trials with the other SGLT2i replicate the results of DAPA-HF, these agents may receive an HF indication as a class.

G.S. reports grants and personal fees from Vifor, grants and non-financial support from Boehringer Ingelheim, personal 

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Canagliflozin and heart failure in type 2 diabetes mellitus

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study

Investigators D-C. Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial

Press release: Farxiga Phase III DAPA-CKD trial will be stopped early after overwhelming efficacy in patients with chronic kidney disease

Investigators D-T. Dapagliflozin and cardiovascular outcomes in type 2 diabetes

Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus

Randomized, double-blind, placebo-controlled, parallel-group established vascular disease, The VERTIS CV Study

Dapagliflozin in patients with heart failure and reduced ejection fraction

Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial

DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction

Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial

Boehringer Ingelheim and Lilly provide update on empagliflozin phase III exercise ability studies in chronic heart failure

Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF)

Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure

Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial

Investigators. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial

Effect of sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure (SOLOIST-WHF Trial)

Lexicon pharmaceuticals provides an update on the sotagliflozin type 2 diabetes program

A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Effects of dapagliflozin in DAPA-HF according to background heart failure therapy

Antihyperglycemic drugs in HF