Adverse events and drug–drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure

ABSTRACT

Introduction

Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug–drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF.

Areas covered

Literature-search-terms in PubMed were ‘adverse event/drug–drug interaction’ and ‘heart failure AND ‘dapagliflozin’ OR ‘empagliflozin’ OR ‘sotagliflozin.’

AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier’s gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.

DDI were mainly studied in healthy volunteers for 3–8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron.

Expert opinion

Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.

KEYWORDS:

• Dapagliflozin
• empagliflozin
• sotagliflozin
• adverse events
• drug–drug interaction
• heart failure

Article highlights

• Although SGLT2-I are increasingly used in patients with diabetes or heart failure, independent studies are rare about adverse events and drug–drug interactions (DDI) of empagliflozin, and dapagliflozin.

• Regarding sotagliflozin, the combined SGLT1/2-I, only a small number of articles reported adverse events and no reports were found on DDI with sotagliflozin.

• There is an urgent need for studies assessing adverse events and DDI of the SGLT2-I with special care on – so far – unrecognized adverse events like sarcopenia

• Pharmacoepidemiologic studies on long-term adverse events, like drug-induced risk for cancer or bone fractures, are desirable.

• Development of evidence-based recommendations for prevention of ketoacidosis would be clinically useful.

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 relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.