Clinical potential relevance of metabolic properties of SGLT2 inhibitors in patients with heart failure

ABSTRACT

Introduction: Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2DM) contributes significantly to end-organ damage and HF-related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2DM. Recently, a novel class of antidiabetic drugs has been introduced: sodium glucose co-trasport-2 inhibitors (SGLT2i). Initially designed for patients with T2DM to reduce kidney blood glucose resorption, SGLT2i rapidly gained attention among HF specialists since they were able to show a beneficial prognostic impact in patients affected by HF and T2DM, even independently from the glycemic control as suggested by the EMPA-REG OUTCOME and CANVAS trials.

Areas covered: The present review focuses on the mechanisms and the current clinical evidence supporting the use of SGLT2i in HF patients with T2DM. Moreover, the SGLT2i pharmacokinetic and pharmacodynamic properties will be presented in order to better understand the rationale and the design of the ongoing clinical trials investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM.

Expert opinion: SGLT2i are emerging as an effective and safe therapy for the treatment of T2DM and current evidence has unexpectedly demonstrated a robust cardiovascular protection in HF patients with T2DM. Therefore, ongoing clinical trials are investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. However, it is methodologically disappointing that the mechanisms underlying the encouraging results in cardiovascular protection of this drug class are still not fully understood. A better understanding of the pharmacokinetic and pharmacodynamic properties of SGLT2i is necessary in order to better determine the effect of this new class of drugs in patients with HF.

KEYWORDS:

• Empagliflozin
• dapagliflozin
• diabetes
• diabetes treatment
• heart failure treatment
• renal glucose transporters
• sodium glucose co-transport-2 (SGLT2) inhibitors

Article highlights

• SGLT2i are a new class of oral antidiabetic drugs that lower plasma glucose by enhancing renal glucose excretion.

• Recently, several clinical trials about SGLT2i such as EMPA-REG OUTCOME and the CANVAS Program demonstrated a protective role on cardiac and renal function, presumably independent of blood glucose control that might be associated to improved prognosis in patients who have HF with or without 2TD.

• Mechanisms underlying cardioprotective function are not completely clarified and the evidence suggests at least three relevant hypotheses: the diuretic hypothesis, the ‘trifty substrate’ hypothesis, and the sodium hypothesis. Moreover, effects on hemodynamics and cardiac structure and function may contribute to the cardiovascular impact of SGLT2i.

• In addition to completed clinical trials, others are currently ongoing to demonstrate the impact of SGLT2i on primary cardiovascular outcomes, such as DECLARE TIMI-58 and VERTIS-CVOT. Recently, the data of the DECLARE TIMI-58 support the hypothesis that SGLT2i might have a positive effect on HF hospitalization and cardiovascular death in diabetic patients.

• According to recent knowledge, a different strategy based on SGLT2i to management of patients with T2DM and established CVD should be considered to improve cardiovascular outcome.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.