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............................................................................................. The SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, ertugliflozin and sotagliflozin were studied in patients with established CV disease in the EMPA-REG OUTCOME and VERTIS-CV trials, with established CV disease or CV risk factors in the CANVAS and DECLARE-TIMI 58 trials, and with CKD and CV risk in the SCORED trial, respectively.293297 A small proportion of patients had a history of HF. Empagliflozin and canagliflozin reduced the primary composite endpoint of major CV adverse events, including CV death or nonfatal MI or non-fatal stroke, and HF hospitalizations in EMPA-REG OUTCOME and CANVAS, respectively.293,294 Empagliflozin also reduced all-cause death or CV death alone.293 The effects on the primary endpoint were driven by the reduction in HF-related events.293,294 In DECLARE-TIMI 58, dapagliflozin did not reduce major CV events but reduced the co-primary efficacy endpoint of CV death or HF hospitalization and HF hospitalization alone.295 In VERTIS-CV, neither the primary major CV event endpoint nor the key secondary outcome of CV death or HF hospitalization were reduced significantly by ertugliflozin, although there was a statistically significant reduction in HF hospitalization and repeated hospitalizations.297,648 In SCORED, sotagliflozin reduced CV deaths and HF hospitalizations.296 In a meta-analysis of these trials and one further trial in patients with CKD (CREDENCE), overall SGLT2 inhibitors reduced HF and CV hospitalization by 22%.649 SGLT2 inhibitors were well tolerated, although they may cause genital fungal skin infections and, rarely, diabetic ketoacidosis.293295 Trial results with dapagliflozin and empagliflozin in patients with HFrEF, with or without diabetes, and with the SGLT1/2 inhibitor sotagliflozin in patients with type 2 diabetes stabilized after hospitalization for acute HF or within 3 days after discharge, further support the administration of these agents (see section 5.3.5 and section 11.3.11).108,109,136 EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58, and VERTIS-CV also showed a reduction in worsening renal function, end-stage renal disease or death from renal causes, with SGLT2 inhibitors. Based on these results, the SGLT inhibitors canagliflozin, dapagliflozin, empagliflozin, ertugliflozin or sotagliflozin are recommended to prevent HF and CV death and worsening kidney function in patients with type 2 diabetes and CV disease and/or CV risk factors, or CKD. Dapagliflozin and empagliflozin are also indicated for the treatment of patients with type 2 diabetes and HFrEF (see section 5.3.5 and section 11.2.4) and sotagliflozin was shown to reduce CV deaths and HF rehospitalizations in patients recently hospitalized for HF.6,296,646,647,650 Metformin is thought to be safe in patients with HF, compared with insulin and sulfonylureas, based on observational studies.651,652 However, it is not recommended in patients with an eGFR <30 mL/ min/1.73 m2 or hepatic impairment because of the risk of lactic acidosis. It has not been studied in controlled outcome trials, to date.6,646 Regarding dipeptidyl peptidase-4 (DPP-4) inhibitors, HF hospitalizations were increased by 27% in one trial with saxagliptin in patients with diabetes.653 However, no difference over placebo for HF events was found with alogliptin, sitagliptin, and linagliptin.654656 Vidagliptin was associated with an increase in LV volumes and a numerically greater number of deaths and CV events in a small trial in patients with diabetes and HF.657 Overall, the effects on mortality or CV events were neutral in the DPP-4 inhibitor trials and meta- analyses.658,659 These drugs are therefore not recommended to reduce CV events in diabetic patients with HF.

Glucagon-like peptide-1 (GLP-1) receptor agonists reduce the risk of MI, stroke, and CV death in patients with diabetes, although probably do not reduce incident HF.6,660 Liraglutide had no effect on LVEF, increased heart rate, and increased serious cardiac events in a randomized placebo-controlled trial in 241 patients with HFrEF with and without diabetes.661 Neutral results on the primary endpoint were found in another trial in 300 patients with a numerical increase in deaths and HF hospitalizations, compared with placebo.662 GLP-1 receptor agonists are therefore not recommended for the prevention of HF events. Insulin is needed in patients with type 1 diabetes and to control hyperglycaemia in some patients with type 2 diabetes, especially when beta-cell function is exhausted. It is a sodium-retaining hormone and concern has been raised that it may exacerbate fluid retention in patients with HF. However, in a RCT that included patients with type 2 diabetes, impaired glucose tolerance, or impaired fasting glucose, insulin did not increase the risk of incident HF.663 Use of insulin was associated with poorer outcomes in retrospective analyses of randomized trials and administrative databases.664,665 If insulin is needed in a patient with HF, the patient should be monitored for evidence of worsening of HF after treatment initiation. Sulfonylureas were associated with a higher risk of HF events in some analyses.666,667 Therefore, they are not a preferred treatment in patients with HF and, if needed, patients should be monitored for evidence of worsening of HF after treatment initiation.6,646 Thiazolidinediones (glitazones) cause sodium and water retention and an increased risk of worsening HF and hospitalization.668 They are contraindicated in patients with HF.

13.2 Thyroid disorders

Assessment of thyroid function is recommended in all patients with HF as both hypo- and hyperthyroidism may cause or precipitate HF.669 Subclinical hypothyroidism and isolated low triiodothyronine levels

Recommendations for the treatment of diabetes in heart failure

Recommendation Classa Levelb

SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin) are recommended in patients with T2DM at risk of CV events to reduce hospitalizations for HF, major CV events, end-stage renal dysfunction, and CV death.293297 I A SGLT2 inhibitors (dapagliflozin, empagliflozin, and sotagliflozin) are recommended in patients with T2DM and HFrEF to reduce hospitalizations for HF and CV death.108,109,136 I A

CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; SGLT2 = sodium-glucose co-transporter 2; T2DM = type 2 diabetes mellitus. aClass of recommendation. bLevel of evidence. ESC 2021

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