SGLT-2 inhibitors for treatment of heart failure in patients with and without type 2 diabetes: A practical approach for routine clinical practice

Highlights

1. SGLT-2i are a promising class of agents for heart failure and chronic kidney disease.
2. An algorithm is provided for prescribing SGLT-2i using a multidisciplinary approach.
3. Tips to prevent common adverse effects with SGLT2i are given.
4. Multidisciplinary guidance can help to offer SGLT-2i to more patients.

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i), initially studied and approved for the treatment of diabetes, are now becoming a promising class of agents to treat heart failure (HF) and chronic kidney disease (CKD), even in patients without diabetes. While the potential benefits in several diseases (usually treated by different medical specialties) is amplifying the interest in these drugs, their use in frail patients with multiple pathologies and on polypharmacy can be complex, requiring a composite multidisciplinary approach. Following a brief overview of the evidence supporting the benefits of SGLT-2i in patients with HF or CKD, we herein provide guidance for prescribing SGLT-2i in daily practice using a multidisciplinary approach. A shared treatment algorithm is presented for initiating an SGLT-2i in patients already being treated for diabetes and HF. Tools to prevent hypoglycemia, blood pressure drop, genital infections, euglycemic diabetic ketoacidosis and eGFR dip are also provided. It is hoped that this practical, multidisciplinary guidance for initiating SGLT-2i in patients with HF and/or CKD, whatever therapy they are currently on, can help to offer SGLT-2i to the largest population of patients possible to provide the most therapeutic benefit.

1. Introduction

Heart failure (HF) affects millions of patients globally, and due to the increased aging of the population is expected to further increase in the future [[1]]. While current treatments have led to a reduction in mortality, at least in patients with HF with reduced ejection fraction (HFrEF), prognosis remains poor and new therapeutic alternatives are needed [[1]]. In this regard, sodium-glucose cotransporter-2 (SGLT-2) inhibitors (SGLT-2i) are a promising class of agents to treat HF. Already approved for type 2 diabetes (T2D), and with a prominent role in current guidelines, some of these drugs have been recently approved for the treatment of HF and CKD. By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose and other profound changes in substrate utilization. However, it is unlikely that the observed benefits in HF can be explained by glucose-lowering alone. Indeed, multiple mechanisms have been proposed to explain the beneficial cardio- and reno-protective effects, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. 

Herein, we briefly overview the supporting evidence documenting the benefits of SGLT-2i in patients with HF or CKD, with or without diabetes. This will be followed by the main objective of this publication, i.e., to provide guidance for prescribing SGLT-2i in daily practice using a multidisciplinary approach, especially in frail patients.

2. SGLT-2i in heart failure

Four major cardiovascular (CV) outcome trials (CVOTs) – EMPA-REG (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS CV (ertugliflozin), have assessed the CV benefits of SGLT-2i in patients with T2D. Reductions of 30%, 33%, 27%, and 35% respectively were seen in the relative risk for hospitalizations for HF (hHF), in these four trials. A meta-analysis of CVOTs on over 34,000 patients reported that SGLT-2i reduced the risk of major adverse CV events (MACE; including CV death, myocardial infarction, and stroke) by 11%, with benefits only for patients with atherosclerotic CV disease

Based on these results, dedicated trials in patients with HF were initiated. In DAPA-HF, 4744 patients with New York Heart Association class II, III, or IV HF and an ejection fraction (EF) of ≤40% were randomized to either dapagliflozin or placebo. Dapagliflozin was superior to placebo in preventing the primary composite endpoint of cardiovascular death, hospitalization for heart failure or urgent heart failure visit (HR 0.74 [95% CI 0.65, 0.85], p < 0.0001). These results prompted the EMA to include the indication for dapagliflozin in the treatment of HFrEF. The EMPEROR-Reduced trial randomized 3730 patients with the same major enrolment criteria used for DAPA-HF to receive empagliflozin or placebo. The primary outcome was a composite of CV death or hHF. After a median of 16 months, the primary outcome was seen in 19.4% of patients receiving empagliflozin vs. 24.7% for placebo (HR 0.75; p < 0.001). A meta-analysis of these two trials suggested a class effect.

Additional evidence for this prospect was recently demonstrated in the SOLOIST-WHF trial in 1222 patients who were hospitalized for worsening heart failure and randomized to sotagliflozin or placebo. Sotagliflozin reduced the primary endpoint (CV death and hospitalizations or urgent visits for heart failure) with an HR of 0.67 (p < 0.001). Interestingly, benefits were seen in patients regardless of whether left ventricular EF was reduced [<50%] or preserved [≥50%]. The EMPEROR-Preserved trial recently reported that empagliflozin significantly decreased the combined risk of CV death or hHF in patients with HF and preserved EF, irrespective of the presence of T2D, with an HR of 0.79 (p < 0.001). A similar study with dapagliflozin (DELIVER; NCT03619213) is still ongoing. It has been postulated that mechanisms for the benefits of SGLT-2 inhibition involve enhanced renal glucose excretion, which promotes weight loss, improved myocardial function, and decreases in uric acid. While reduction in blood pressure may have some effects, it is unclear what role the slight reduction in blood pressure may have in these patients.

3. SGLT-2i in chronic kidney disease

Several CVOTs have shown that SGLT-2i have reno-protective effects. Following the CANVAS trials, the CREDENCE study randomized 4401 patients with T2D, an eGFR of 30 to <90 ml/min/ 1.73 m² and substantial albuminuria to canagliflozin 100 mg or placebo. Of note, the annual decline in eGFR was slower with canagliflozin (−1.72 vs. -4.33 ml/min/1.73 m²) and the absolute benefits on renal outcomes were most prominent in patients with lower eGFR at baseline. In the VERTIS CV trial, 8246 patients with type 2 diabetes and established atherosclerotic CV disease were randomized to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo as add-on therapy. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant, or renal death was lower with ertugliflozin than placebo, HR 0.66 (p < 0.01) .

SGLT-2i benefits on renal function were particularly interesting in the DAPA-CKD study, as 32.5% of studied patients did not have diabetes at enrollment. This trial randomized 4304 patients with eGFR of 25 to 75 ml/min/1.73 m² and UACR of 200–5000 to dapagliflozin 10 mg or placebo. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal or CV causes. Dapagliflozin was superior to placebo in preventing the primary composite endpoint of ≥50% sustained decline in eGFR, reaching end-stage kidney disease, cardiovascular or renal death with a HR of 0.61 (95% CI 0.51, 0.72; p < 0.0001). The composite endpoint of death from CV causes or hHF also favored dapagliflozin (HR 0.71; p = 0.009) and there were also fewer deaths among those treated with dapagliflozin (4.7% vs. 6.8%; HR 0.69; p = 0.004). Importantly, benefits were seen in patients both with and without T2D. These results prompted the EMA to include the indication for dapagliflozin in the treatment of CKD.

4. Practical guidance for daily practice

4.1 Initiating an SGLT-2i in patients being treated for T2D

There are currently few recommendations for the use of SGLT-2i in patients with HFrEF with or without type 2 diabetes, although the Canadian Cardiovascular Society (CCS) guidelines have provided some general guidance in such patients as have the Association of British Clinical Diabetologists (ABCD) and Diabetes UK. In addition, the updated ESC guidelines on HF have indicated that SGLT-2i are to be considered to have Level IA evidence for their use in HF patients with reduced EF, even if no specific recommendations were made regarding their initiation. Very recently, the American College of Cardiology also issued guidelines on optimizing the decision pathway for patients with HFrEF. However, none of these guidelines provides support for initiating an SGLT-2i for HFrEF in a patient already taking medicines for diabetes.

Though sharing SGLT-2i initiation with the endocrinologist or general practitioner who is already caring for the diabetic patient is fundamental, the interaction may take time. Our purpose is therefore to provide a few but important suggestions on how to initiate an SGLT-2i in a diabetic patient with HFrEF, especially when frailty is present. Beyond the possible (although rare) risk of euglycemic diabetic ketoacidosis (eDKA) described below, the major risk in patients with diabetes is induction of hypoglycemia, usually associated with higher mortality rates. Non-endocrinologists should therefore carefully evaluate a series of parameters before initiation of another medicine for diabetes which might induce a significant adverse event. As seen in Table 1 and Fig. 1, after an accurate targeted anamnesis, the first check should regard the diabetes medicines already in use.

Since sulfonylurea receptor agonists (SURa: sulfonylureas and glinides) and insulin are the only diabetes medicines able to induce hypoglycemia, their absence in the diabetes treatment plan might ensure the absence of this risk, independently of the other medicines already present in the treatment plan (metformin, DPP-4is, GLP-1 RAs, pioglitazone, acarbose, alone or in combination). On the contrary, if SURa or insulin are present, the risk of inducing hypoglycemia is possible, and caution should be taken, especially in frail patients. The possible risk of hypoglycemia induced by the initiation of an SGLT-2i depends on several parameters, including efficacy, starting glucose control, and the patient’s current risk of hypoglycemia, which should be explored in depth with a specific anamnesis (including possible signs suggesting hypoglycemic episodes). Since SGLT-2i mostly lose their glucose-lowering effect when eGFR is lower than 45 ml/min/1.73 m² (below this threshold these medicines must be suspended if prescribed “only” for diabetes), the addition of an SGLT-2i is not expected to further lower glucose levels and is therefore safe, unless the patient is already experiencing hypoglycemic episodes. The second important parameter to be monitored is glucose control, namely, HbA_1c.

Since SGLT-2i are expected to lower HbA_1c by not more than 0.8%, their addition in patients already treated with other medicines but with an HbA_1c ≥ 7.5% can be considered safe. The most important parameter that should be verified before initiating an SGLT-2i is the presence of hypoglycemic episodes. The evaluation of reported self-monitored blood glucose (SMBG) is fundamental before initiating treatment. In case of hypoglycemic episodes, even if anamnestically collected, glucose lowering medications should be reduced by up to 50%. This reduction should also be applied to patients taking SURa and/or insulin with an eGFR higher than 45 ml/min/1.73 m² and HbA_1c < 7.5% even if there are no hypoglycemic episodes. A simple algorithm that summarizes the above information is shown in Fig. 1. Collaboration with the endocrinologist or general practitioner in prescribing diabetes therapy, is obviously essential.

Table 1Parameters to be checked before initiating an SGLT-2i in a patient with diabetes who is already treated with glucose-lowering medication to avoid hypoglycemia.