Heart failure hospitalization with SGLT-2 inhibitors: a systematic review and meta-analysis of randomized controlled and observational studies

ABSTRACT

Introduction: Heart failure (HF) in type 2 diabetes mellitus (T2DM) poses a significant increase in mortality. Until recently, anti-diabetic drugs have not been shown to reduce hospitalization due to heart failure (hHF). While thiazolidinedione class and saxagliptin has shown a significantly increased risk, sodium-glucose linked co-transporter 2 inhibitors (SGLT-2Is) have demonstrated a significant reduction in the risk of hHF.

Areas covered: We systematically searched the database of PubMed, Embase, ClinicalTrials.gov, and International conference presentation up to 25 December 2018 and retrieved all the studies that were conducted for ≥24 weeks and explicitly reported hHF outcome. Subsequently, we conducted the meta-analysis to study the effect of SGLT-2Is on hHF outcome in randomized controlled trials (RCTs), observational studies, and both.

Expert opinion: The meta-analysis of RCTs (N = 34,322), observational studies (N = 15,36,339), and both (N = 15,70,661) demonstrated a significant decrease in hHF (OR 0.70, 0.64, 0.66, respectively, all p = 0.000) with SGLT-2Is compared to placebo or other anti-diabetes drugs in T2DM. A significant benefit in hHF (OR 0.68, p = 0.000) is also observed in patients with established HF (N = 3891) in sub-group meta-analysis of RCTs. Ongoing dedicated HF trials will further enlighten the merits of SGLT-2Is in patients with established heart failure (preserved or reduced) with or without T2DM.

KEYWORDS:

• Type 2 diabetes
• heart failure hospitalization
• SGLT-2 inhibitors
• cardiovascular outcome

Article highlights

• Type 2 diabetes mellitus and heart failure together pose a major public health risk as it has a much poorer outcome compared to either condition alone.

• Modern anti-diabetic drugs have diverse risks and benefits with regard to heart failure outcomes. While among the DPP-4 inhibitors both saxagliptin and alogliptin are not recommended in patients with cardiac and renal disease with the anticipation of the increase in heart failure rates, both sitagliptin and linagliptin have not shown any such signals in dedicated cardiovascular outcome trials. GLP-1 receptor agonists have also failed to demonstrate any benefit on heart failure outcomes so far.

• SGLT-2 inhibitors have significantly demonstrated a reduction in risk of heart failure hospitalization in patients with type 2 diabetes, regardless of baseline presence or absence of established heart failure. However, this needs to be convincingly demonstrated in patients with established heart failure through a dedicated heart failure trial.

• Future trials of SGLT-2 inhibitors in the patient with or without diabetes, with heart failure (with reduced or preserved ejection fraction, assessed by echocardiography) will further enhance our knowledge on this contemporary issue.

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.

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Funding

This paper was not funded.