An update on the safety of insulin-GLP-1 receptor agonist combinations in type 2 diabetes mellitus

ABSTRACT

Introduction

Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time.

Areas covered

There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile.

Expert opinion

FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.

KEYWORDS:

• Basal insulin (bi)
• fixed-ratio insulin-glp-1 receptor agonist combination (frc)
• glucagon-like peptide-1 receptor agonist (glp-1 ra)
• hypoglycemia
• insulin degludec
• insulin glargine
• liraglutide
• lixisenatide
• type 2 diabetes (t2dm)
• weight loss

Article highlights

• Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) take advantage of complementary mechanisms of action of their two components and are able to address most of the pathological processes linked with the development of type 2 diabetes (T2DM).

• There are currently 3 FRC formulations available on the market: iGlarLixi containing 100 units/ml of insulin glargine and 50 mcg/ml (pen A) or 33 mcg/ml (pen B) of lixisenatide and IDegLira containing 100 units/ml of insulin degludec and 3.6 mg/ml of liraglutide.

• iGlarLixi and IDegLira have better effect on glycemic control than their individual components when initiated in T2DM patients inadequately controlled on oral therapy. Initiation of both FRCs also leads to better glycemic control in comparison to continued therapy with a GLP-1 RA or basal insulin up-titration and has similar effect on glycemic control than initiation of a basal-bolus regimen.

• The insulin driven weight gain can be substantially mitigated by the weight reducing effects of the GLP-1 RA component and, conversely, GI adverse effects linked with the GLP-1 RAs can be reduced by the gradual up-titration of the FRC dose.

• FRCs thus represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM.

Declaration of interest

P Novodvorský has served on speaker panels for Novo Nordisk, Eli Lilly, Sanofi, on advisory panels for Sanofi, received honoraria or consulting fees from Merck and Eli Lilly and received travel grants from Sanofi and Eli Lilly. M Haluzík has served on advisory panel for Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Mundipharma; and has served as a consultant for Eli Lilly, Novo Nordisk, Sanofi, Astra Zeneca, Mundipharma; and has received research support for AstraZeneca, Eli Lilly, Bristol-Meyers Squibb; and has received honoraria or consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Johnson. The authors have no other 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

Supported by Ministry of Health, Czech Republic - conceptual development of research organization („Institute for Clinical and Experimental Medicine – IKEM, IN 00023001“).