-2

≥60–<80 mg/dL(≥3.3–<4.4 mmol/L)

+2

>110–≤140 mg/dL(>6.1–≤7.8 mmol/L)

+4

>140 mg/dL(>7.8 mmol/L)

-2 to -4

<60 mg/dL (<3.3 mmol/L) or occurrence of ≥2

symptomatic hypoglycaemia or

1 severe hypoglycaemia episode in the preceding week

No change

80–110 mg/dL(4.4–6.1 mmol/L)

Glycaemic target:

Inadequately controlled by basal insulin (daily dose range 20–50 U) combined with metformin ± sodium glucose co-transport

2 inhibitor (SGLT2i)

Objective

Primary efficacy endpoints

Study design

Introduction

Affiliations: 1Division of Systems Medicine, School of Medicine, University of Dundee, Dundee, UK; 2Al Hada Military Hospital, Taif, Saudi Arabia; 3Department of Endocrinology and Metabolic Diseases, Ankara University Faculty of Medicine, Ankara, Turkey; 4Dr. Mohan’s Diabetes Specialities Centre & Madras Diabetes Research Foundation, IDF Centre of Excellence in Diabetes Care & ICMR Centre for Advanced Research on Diabetes, Chennai, India; 5Instituto de Diabetes Obesidad y Nutrición S.C., Cuernavaca, Morelos, Mexico; 6Hospital Universitario de La Ribera, Alzira, Spain; 7Faculty of Medicine of the University of Belgrade, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia; 8Sanofi, Buenos Aires, Argentina; 9Diabetes Medical Operation Department, Sanofi, Chilly-Mazarin, France; 10Biostatistics and Programming Department, Sanofi, Chilly-Mazarin, France; 11†Sanofi US, Bridgewater, NJ, USA; 12Sanofi, Paris, France; 13Dallas Diabetes Research Center at Medical City, Dallas, TX, USA

Authors:Rory J. McCrimmon MD1, Saud Al Sifri MD2, Rifat Emral MD3, Viswanathan Mohan MD4, Leobardo Sauque-Reyna MD5, Carlos Trescolí MD6, Nebojsa Lalic MD7, Agustina Alvarez MD8, Nacima Demil MD9, Mathieu Coudert MSc10, Alka Shaunik MD11, Mireille Bonnemaire MD12, Julio Rosenstock MD13,on behalf of the SoliMix Trial Investigators

†At time the study was conducted. Current affiliation: CSL Behring, King of Prussia, PA, USA

Advancing therapy with iGlarLixi versus premix BIAsp 30 in basal insulin-treated type 2 diabetes: Design and baseline characteristics of the SoliMix randomized controlled trial

Conclusions

AbbreviationsADA, American Diabetes Association; AE, adverse event; BIAsp 30, biphasic insulin aspart 30 (30% insulin aspart and 70% insulin aspart protamine); BMI, body mass index; FRC, fixed-ratio combination; GLP-1 RA, glucagon-like peptide-1 receptor agonist; iGlar, insulin glargine 100 U/mL; HbA1c, glycated haemoglobin; iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the GLP-1 RA, lixisenatide; Lixi, lixisenatide; NPH, neutral protamine hagedorn; OAD, oral antihyperglycaemic drug; SD, standard deviation; SGLT2i, sodium glucose co-transporter 2 inhibitor; SMPG, self-monitored plasma glucose; T2D, type 2 diabetes

This infographic represents the opinions of the authors. For a full list of declarations, including funding and author disclosure statements,please see the full text online. Full manuscript

vs

x1

SoliMix is the first randomized controlled trial to directly compare the efficacy and safety of an FRC of basal insulin and GLP-1 RA, iGlarLixi, with a premix insulin analogue, biphasic insulin aspart 30 (30% insulin aspart and 70% insulin aspart protamine) (BIAsp 30), in people with T2D uncontrolled on basal insulin plus one or two oral antihyperglycaemic drugs (OADs)

The study design and baseline characteristics of SoliMix are described here

Population

Start dose: 20 U iGlar/10 μg Lixi if previous iGlar* dose was <30 U (10–40 U Pen)Start dose: 30 U iGlar/10 μg Lixi if previous iGlar* dose was ≤50 U (30–60 U Pen)

Weekly dose adjustments for iGlarLixi(based on three once-daily fasting self-measured plasma glucose (SMPG) measurements)

Weekly dose adjustments for BIAsp 30(based on three twice-daily pre-meal SMPG measurements)

Median of fasting SMPG values from the last 3 measurements

iGlarLixi† dose adjustments (U/day)

*If a twice-daily basal insulin or insulin glargine 300 U/mL was used, the total daily dose previously used should be reduced by 20% to choose the iGlarLixi starting dose. If any other basal insulin was used, the same rule as for iGlar should be applied; †The U/day refers solely to the iGlar component of iGlarLixi

*BIAsp 30 titration utilized pre-dinner SMPG values for breakfast dose adjustment and pre-breakfast SMPG values for dinner dose adjustment

*Defined as severe cognitive impairment requiring external assistance for recovery

No change

80–110 mg/dL(4.4–6.1 mmol/L)

Glycaemic target:

Start dose: same dose as previous basal insulin dose on a unit-to-unit basis divided into two daily doses

The lowest pre-meal SMPG values of the last 3 days*

BIAsp 30 dose adjustment (U)

-2

<80 mg/dL (<4.4 mmol/L)

+2

111–140 mg/dL(6.2–7.8 mmol/L)

+4

141–180 mg/dL (7.9–10.0 mmol/L)

+6

>180 mg/dL(>10.0 mmol/L)

Non-inferiority of iGlarLixi to BIAsp 30 in HbA1c reduction from baseline to Week 26 (non-inferiority margin of 0.3 %)

Superiority of iGlarLixi versus BIAsp 30 in bodyweight change from baseline to Week 26

HbA1c

Patient-reported outcomes

Treatment-Related Impact Measure Diabetes (TRIM-D) scoresPatient- and physician-rated Global Treatment Effectiveness Evaluation (GTEE) scores

Key secondary efficacy endpoints

Other secondary efficacy endpoints

Safety endpoints

The proportion of participants reaching HbA1c target <7 % without weight gain at Week 26

The proportion of participants reaching HbA1c target <7 % without weight gain at Week 26 and without hypoglycaemia (<70 mg/dL [<3.9 mmol/L]) during the treatment period

Superiority of iGlarLixi versus BIAsp 30 in HbA1c reduction from baseline to Week 26HbA1c

Change in total insulin dose from baseline to Week 26

Change in fasting plasma glucose from baseline to Week 26

Proportion of participants achieving HbA1c <7 % at Week 26

Prospective, head-to-head, randomized study, which is the gold standard for comparing two therapies

The study involved a clinically relevant population with participants recruited from countries and regions where premix insulin is most often used

Patient reported outcomes assessed

The first trial to directly compare an FRC of basal insulin and GLP-1 RA with a premix insulin

Only metformin and SGLT2i permitted as concurrent medications

Open-label design

Strengths and limitations

0.43+0.15

0.43+0.14

HbA1c

HbA1c of ≥7.5 % and ≤10 %

(≥58.5–≤85.8 mmol/mol)

Baseline characteristics

Overall, baseline characteristics did not differ between the two treatment groups

Race

iGlarLixi (N=443) BIAsp 30 (N=444)

Strengths andlimitations

Introduction Study design ConclusionsBaselinecharacteristics

Adults (≥18 years)

T2D

Hypoglycaemia <70–≥54 mg/dL(<3.9–≥3.0 mmol/L)

Severehypoglycaemia*

<54 mg/dL(<3.0 mmol/L)

Treatment-emergent adverse events (AEs), serious AEs

Level 1 Level 2 Level 3

!

ADA definition

Data from prospective randomized studies, such as the present study, are important for clinical practitioners as they are the gold standard for evaluating new therapies with improved benefit–risk profiles, enabling individualization of therapy

These new therapies should provide people with options involving reduced treatment complexity and therapeutic burden

Results from this trial will provide a robust level of evidence to support clinical decisions when basal insulin therapy needs to be advanced in people with uncontrolled T2D, and may inform future treatment guidelines

For people with type 2 diabetes (T2D) on basal insulin who fail to reach their recommended glycaemic targets, options for treatment advancement are:• Basal insulin + progressive addition of rapid-acting insulin• Premix insulin• Basal insulin + glucagon-like peptide-1 receptor agonist (GLP-1 RA)• Fixed-ratio combination (FRC) of basal insulin + GLP-1 RA

iGlarLixi is a once-daily titratable FRC of basal insulin glargine 100 U/mL (iGlar) and the GLP-1 RA, lixisenatide (Lixi), which offers an alternative option for treatment intensification

A systematic literature review and network meta-analysis showed that iGlarLixi therapy was associated with greater HbA1c reductions compared with premix and basal plus prandial insulin regimens, in addition to favourable bodyweight changes versus premix insulin regimens

Ischaemicstroke

00.5Comorbidities

Peripheralartery disease

0.5 2.0

Insulin degludec

4.3 4.7Prior basal

insulin

Black orAfrican American

0.2 0.2

Heartfailure

2.5 1.8

Insulin detemir

7.7 7.0

SGLT2i alone

0 0.5

Asian

38.7 30.9

15.1 15.1

Diabeticretinopathy

Insulin glargine 300 U/mL

22.6 20.7

Metformin +SGLT2i alone

23.5 22.5

American Indian or Alaska Native

1.61.8

Diabetic nephropathy

10.2 9.2

NPH

23.0 18.4

Metformin + other

0.2 0.5

White

58.8 66.1

Diabeticneuropathy

26.9 28.6

Insulin glargine 100 U/mL

42.4 49.2

Metformin alone

76.3 76.6

Background OADs

HbA1c

T2D

Weeks

iGlarLixi once daily (N=443) Follow-up(3 days)

BIAsp 30 twice daily (N=444) Follow-up(3 days)

End of treatment (Week 26)

Randomization 1:1

Open-label, randomized treatment period (26 weeks)

Screening (1–2 weeks)

-2

Visits 1

0

2

2

3

4

4

6

5

8

6

10

7

12

8

18

9

26

10 11

on-site visit; phone visit

iGlarLixi(N=443) 49.4%

50.9%

Sex, % female

29.7±4.7

30.0±5.1

Mean ± SDBMI, kg/m2

8.6±0.7

8.6±0.7

71±7

70±7

Mean ± SDHbA1c

HbA1c

13.0±7.1

13.0±7.4

Mean ± SDduration ofT2D, years

59.8±10.3

59.8±10.0

Mean ± SDage, years

% mmol/mol

BIAsp 30(N=444)

iGlarLixi

BIAsp 30