Success story of SGLT-2 inhibitors - impressive evidence base.

The SGLT(“sodium glucose-linked transporter”)-2 inhibitors have demonstrated cardioprotective effects in addition to antidiabetic effects. The current evidence supports the benefit of several agents of SGLT-2-i in the treatment of heart failure in both patients with and without diabetes. More recently, evidence of efficacy of HFrEF has been extended to HFmrEF and HFpEF.

Heart failure is a common complication of diabetes with a prevalence of up to 30% in the age group of diabetics over 65 years [1,2]. Clinically, heart failure is present when there is an objectifiable cardiac dysfunction that is either associated with dyspnea, fatigue, and/or fluid retention or, in the case of asymptomatic left ventricular heart failure, is present without accompanying symptoms [3]. In cases of clinical suspicion and abnormalities in ECG, determination of natriuretic peptides (BNP or NT-proBNP) is recommended [4]. If NT-proBNP >125 pg/ml or BNP >35 pg/ml, transthoracic echocardiography is indicated [4,5]. Based on the findings of left ventricular ejection fraction, heart failure (HF) is classified into the following three groups: “Heart failure with reduced ejection fraction” (HFrEF, reduced ejection fraction), “HF with mildly reduced EF” (HFmrEF, intermediate ejection fraction), and “HF with preserved EF” (HFpEF, preserved ejection fraction) [6].

SGLT-2-i – important landmark studies at a glance

A first milestone in the success story of SGLT-2 inhibitors (SGLT-2i) (Fig. 1) occurred with the publication of the results of the EMPA-REG-OUTCOME study [7,19]. It has been impressively demonstrated that in individuals with type 2 diabetes and high cardiovascular risk, treatment with empagliflozin significantly improves cardiovascular outcomes [6]. Empagliflozin reduced the incidence of heart failure-related hospitalizations by 35%. A few years later, in 2019, the results of the DAPA-HF study were presented for the first time [8]. These demonstrated that dapagliflozin as an add-on to established heart failure (HF) therapy resulted in significant reductions in cardiovascular and all-cause mortality and HF hospitalization rates. Furthermore, clinical symptoms and quality of life improved. And in 2020, the EMPEROR-REDUCED trial provided evidence that empagliflozin can achieve a similarly encouraging outcome [9]. A meta-analysis of the two studies showed that these agents can reduce HF-related hospitalization rates, all-cause mortality, and cardiovascular mortality [10].

The latest data are from the EMPULSE trial and suggest that empagliflozin is effective and safe when administered as an add-on to heart failure patients while still hospitalized [11].

The results of the EMPEROR-PRESERVED (empagliflozin) and DELIVER (dapagliflozin) trials demonstrated for the first time an evidence-based benefit also for heart failure patients with an EF >40%. A statistically significant improvement in the combined end point consisting of cardiovascular mortality and HF hospitalization rate (independent of T2DM) (Fig. 2) was achieved [12–14]. This closed an important treatment gap.

Regarding canagliflozin, data on heart failure are available from the CANVAS study or from the CANVAS-R substudy (n=5812) [15]. 14.4% of these type 2 diabetics had a history of heart failure. HF-related hospitalizations were significantly reduced with canagliflozin (HR: 0.72; 95% CI: 0.55-0.94; p=0.0148).

SGLT-2-i are recommended by SGED as first-line therapy in T2D.

In the updated treatment recommendations of the Swiss Society of Endocrinology and Diabetology (SGED) published in 2023, a combination of metformin and an SGLT-2-i or a GLP-1 receptor agonist (GLP-1-RA) is suggested for the initial drug treatment of type 2 diabetes for all patients right from the start [16]. This recommendation is based on the fact that SGLT-2-i are an effective treatment option for heart failure, regardless of _HbA1c level. According to expert opinion, patients can benefit most if they receive an SGLT-2-i as an add-on as soon as possible after being diagnosed with heart failure [16]. In type 2 diabetics, when the combination of metformin plus SGLT-2-i is not sufficient to achieve the target _HbA1c, it is suggested that a GLP-1 RA be added as a third medication. Empirical evidence from clinical practice in Europe and the United States demonstrates that this triple therapy is the best option compared with other combinations to reduce 3-point MACE (“major adverse cardiac event”), all-cause mortality, and heart failure [17,18]. In general, SGLT-2-i are considered safe. Adverse effects more commonly reported in studies include genital fungal infections and urinary tract infections. In contrast, serious adverse events such as ketoacidosis, amputations (only with canagliflozin), and Fournier’s gangrene have been described only occasionally [6].

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Pandey A, et al: Biomarker-Based Risk Prediction of Incident Heart Failure in Pre-Diabetes and Diabetes. JACC Heart Fail 2021. 9(3): 215-223.
McDonagh TA, et al: 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42(36): 3599-3726.
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McMurray JJV, et al: Dapagliflozin in patients with heart failure and reduced ejection fraction. NEJM 2019; 381(21): 1995-2008.
Packer M, et al: Cardiovascular and renal outcomes with empagliflozin in heart failure. NEJM 2020; 383(15): 1413-1424.
Zannad F, et al: SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020; 396(10254): 819-829.
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Neal B, et al; CANVAS Program Collaborative Group Canagliflozin and cardiovascular and renal events in type 2 diabetes. NEJM 2017; 377(7): 644-657.
16 Gastaldi G, et al: Swiss recommendations of the Society for Endocrinology and Diabetes (SGED/SSED) for the treatment of type 2 diabetes mellitus. Swiss Med Wkly 2023; 153: 40060.
Jensen MH, et al: Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality for Widely Used Antihyperglycemic Dual and Triple Therapies for Type 2 Diabetes Management: A Cohort Study of All Danish Users. Diabetes Care 2020; 43(6): 1209-1218.
Dave CV, et al: Risk of Cardiovascular Outcomes in Patients With Type 2 Diabetes after addition of SGLT2 Inhibitors versus Sulfonylureas to baseline GLP-1RA Therapy. Circulation 2021; 143(8): 770-779.
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