Research summary

Introduction

Conclusions

Affiliations: 1Endocrinology and Nutrition Unit, Segovia General Hospital, Segovia, Spain. 2Dasman Diabetes Institute, Kuwait City, Kuwait. 3Tameside and Glossop Integrated Care NHS Foundation Trust, Ashton-under-Lyne, UK. 4University of Manchester, Manchester, UK. 5Department of Endocrinology, Zhongshan Hospital, Fudan University, Shanghai, China. 6Dallas Diabetes Research Center at Medical City, Dallas, Texas, USA.

Authors:Fernando Gomez-Peralta, MD1, Ebaa Al-Ozairi, MD2, Edward B. Jude, MD3,4, Xiagying Li, MD5, Julio Rosenstock, MD6

AbbreviationsAE, adverse event; BIAsp 30, biphasic insulin aspart 30 (30% insulin aspart and 70% insulin aspart protamine); IDeg, insulin degludec; IDegLira, an FRC of insulin degludec and the GLP-1 RA liraglutide; iGlarLixi, an FRC of insulin glargine 100 U/mL and the GLP-1 RA lixisenatide; FRC, fixed-ratio combination; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; OAD, oral antihyperglycemic drugs; RCT, randomized controlled trial; RWE, real-world evidence; T2D, type 2 diabetes

References1. National Institute for Clinical Excellence (NICE). Available from https://www.nice.org.uk/guidance/ng28/resources/

-type-2-diabetes-in-adults-management-pdf-1837338615493 [Accessed 30 June 2020]2. American Diabetes Association. Diabetes Care. 2021;44:S111–S1243. Davies et al. Diabetes Care. 2018;41:2669–27014. Ilag et al. Clin Ther. 2007;29 Spec No:1254–705. Jin et al. J Diabetes. 2016;8:405–136. Kaneko et al. Diabetes Res Clin Pract. 2015;107:139–477. Liebl et al. Diabetes Obes Metab. 2009;11:45–528. Rodbard et al. Diabetes Obes Metab. 2016;18:274–809. Rosenstock et al. Diabetes Care. 2008;31:20–510. Taneda et al. J Diabetes. 2017;9:243–711. Jude et al. Diabetes Obes Metab. 2020; doi:10.1111/dom.14298 [E-pub ahead of print]12. Khunti et al. Diabetes Obes Metab. 2016;18:401–913. Satoh et al. PLoS One. 2018;13:e019816014. Nauck et al. Nat Rev Endocrinol. 2011;7:193–515. Aroda et al. Diabetes Care. 2016;39:1972–8016. Rosenstock et al. Diabetes Care. 2016;39:2026–3517. Blonde L et al. Diabetes Care. 2019;42:2108–1618. Gough et al. Lancet Diabetes Endocrinol. 2014;2:885–9319. Buse et al. Diabetes Care. 2014;37:2926–3320. Linjawi et al. Diabetes Ther. 2017;8:101–1421. Rayner et al. Diabetes Obes Metab. 2021;23:136–4622. Home et al. Diabetes Obes Metab. 2020;22: 2179–8823. Watada et al. Diabetes Ther. 2020;11:331–924. McCrimmon R et al. Diabetes Obes Metab. 2021; doi: 10.1111/dom.14354 [E-pub ahead of print]

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Introduction Research summary Conclusions

Titratable fixed‐ratio combination of basal insulin plus a glucagon‐like peptide‐1 receptor agonist: A novel, simplified alternative to premix insulin for type 2 diabetes

To discuss the unmet needs of people with T2D treated with premix insulin and provide evidence to support FRCs of basal insulin and GLP-1 RAs as an alternative treatment option

Objectives

Despite advances in T2D therapy, the proportion of people with diabetes reaching HbA1c targets remains poor

Due to the progressive nature of T2D, many individuals not controlled with OADs will require advancement to injectable therapy, with some requiring further intensification of their injectable therapy

Post hoc analyses of the LixiLan-G trial also show that iGlarLixi provides comparable efficacy and safety regardless of SGLT2i use2

Premix insulins remain frequently used as an option for initiation of insulin therapy or intensification from basal insulin1 despite the increased risk of hypoglycemia and weight gain compared with basal insulin,4 and limited published evidence for sustained efficacy

FRCs of basal insulin and GLP-1 RAs provide a novel alternative to premix insulin for therapy intensification

Evidence from RCTs shows substantial HbA1c reductions in individuals previously uncontrolled on basal insulin 24–26 weeks after switching to premix insulin5–10

However, premix insulins are also associated with greater weight gain and greater hypoglycemia risk compared with basal insulin4

Comparative studies of premix insulin versus basal insulin with or without prandial insulin

Real-world evidence of poor glycemic control with premix insulin

Rationale for combination therapy with basal insulin and GLP-1 RAs

Novel titratable FRCs of basal insulin and GLP-1 RAs

Evidence on premix insulin versus FRCs of basal insulin and GLP-1 RAs

Head-to-head RCT comparing iGlarLixi with premix insulin

Contrary to data from RCTs, numerous RWE studies have shown that glycemic control remains less than optimal after initiating or switching therapy to premix insulin11-13

The efficacy and safety of these FRCs has been established in the LixiLan (iGlarLixi)15–17 and DUAL (IDegLira)18–20 RCT programs

In a systematic review and network meta-analysis, individuals intensified to iGlarLixi demonstrated greater estimated differences in HbA1c reduction, lower weight gain, and suggested lower rates of confirmed and documented symptomatic hypoglycemia compared with premix insulin22

FRCs, such as iGlarLixi, may offer better glycemic control, lower risk of hypoglycemia without weight gain, and provide a more convenient and simplified therapy option than premix insulin, potentially leading to improved treatment adherence and quality of life

SoliMix is a 26-week, open-label, randomized, active-controlled, parallel-group, multicenter study comparing the efficacy and safety of iGlarLixi versus premix insulin analog (BIAsp 30)24

Combination therapy with a basal insulin and a GLP-1 RA provides complementary mechanisms of action+

Primarily reduces fasting plasma glucose, mainly by

suppressing hepatic glucose production14

Basal insulin

Improve glycemic control by stimulating insulin release and suppressing glucagon secretion.

Additionally, short-acting GLP-1 RAs can delay gastric emptying, helping to reduce postprandial

glucose14

GLP-1 RAs

iGlarLixi insulin glargine 100 units/mLand lixisenatide

IDegLira insulin degludec 100 units/mL and liraglutide

Currently available FRCs for control of T2D consist of:

Both iGlarLixi and IDegLira demonstrated greater HbA1c reductions versus their individual components, with similar or lower risk of hypoglycemia and favorable weight-change profiles compared with their basal insulin component and fewer gastrointestinal AEs versus their GLP-1 RA component15–21

IDegLira

IDeg

Premix insulinIn a post-hoc analysis of individuals

switching from premix insulin to IDegLira or IDeg, people who switched to IDegLira experienced a decrease in mean HbA1c and bodyweight23

Head-to-head comparisons of FRCs and premix insulin are lacking

HbA1c

The greater likelihood of weight gain and hypoglycemia, combined with the need for multiple daily injections and frequent self-monitoring of blood

glucose with premix insulin, may suggest that the efficacy observed in RCTs is difficult to achieve in real-world practice

While indirect evidence suggests that FRCs of basal insulin and GLP-1 RA offer benefits compared with premix insulin, head-to-head RCTs comparing both approaches are currently lacking. This evidence gap will start to be addressed by the first head-to-head trial of iGlarLixi versus BIAsp 30

While such prospective RCTs are invaluable in providing comparative data on efficacy and safety of therapies, results from RCTs are not always generalizable to real-life clinical practice due to stringent follow-ups, protocols, titration algorithms,

and highly selected populations. Further real-world comparative effectiveness studies would complement the aforementioned RCT and explore whether the results

are maintained in a real-life clinical setting

T2D

T2D

26-week

GLP-1 RA Basal insulin Basal + prandial insulinPremix insulinBasal insulin + GLP-1 RA or a fixed-ratio

combination (FRC)

This study will address a question that has previously not been properly tested in a prospective RCT, namely assessing the comparative efficacy

and safety of advancing basal insulin therapy by switching to a twice-daily premix insulin analog regimen, such as BIAsp 30, or by switching to

a simpler once-daily FRC, such as iGlarLixi

versus

T2D

HbA1c of ≥7.5 %(≥58.5 mmol/mol)

and ≤10 %(≤85.8 mmol/mol)

Failed to reach glycemiccontrol with basal insulinplus one or two OADs

iGlarLixi

BIAsp 30

Injectable therapy options include:1–3