CPD: Superior HbA1c reduction with iGlarLixi

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Superior HbA1c reduction with iGlarLixi

Type 2 diabetes (T2DM) is a progressive disease, associated with microvascular complication such as retinopathy, nephropathy, and neuropathy, as well as macrovascular complications including myocardial infarction. To prevent these complications, prompt treatment intensification is recommended.2,4,5

Despite the high risk, studies show that it can take up to seven years before treatment intensification is initiated, further increasing the risk of diabetes-related complications. See box 1 for treatment intensification recommendations.2

Treatment intensification options

Guidelines recommend progressive addition of rapid-acting insulin to patients’ existing basal insulin regimen, multiple doses of premix insulin, addition of a glucagon-like peptide-1 receptor agonists (GLP-1 RA) or switching to a once-daily fixed-ratio combination (FRC) of basal insulin and a GLP-1 RA as intensification options, said Dr Adri de Kok, one of South Africa’s leading experts in diabetes care.1,3

Dr de Kok was the keynote speaker at the South African launch of of iGlarLixi (see box 2). The combination offers a once-weekly, singleinjection option for treatment intensification.3

Dr de Kok discussed the findings of the Advancing therapy in suboptimally controlled basal insulin-treated type 2 diabetes: Clinical outcomes with iGlarLixi versus premix BIAsp 30 in the SoliMix randomized controlled trial, published in the June edition of Diabetes Care.3

SoliMix is the first head-to-head clinical trial comparing the safety and efficacy of iGlarLixi versus premix insulin (BIAsp30 [30% insulin aspart + 70% insulin aspart protamine]), plus one or two oral antidiabetic agents (OADs), in adult patients with insufficiently controlled T2DM.1

Solimix study design

SoliMix was a 26-week, open-label study involving 89 centres in 17 countries. Participants (n=887) with T2DM, suboptimally controlled (HbA1c ≥7.5% and ≤10%) on basal insulin were randomised to once-daily iGlarLixi (n=443) or twice-daily BIAsp 30 (n=444).1

Primary efficacy endpoints

Primary efficacy endpoints were non-inferiority in HbA1 c reduction (margin 0.3%) or superiority in bodyweight change for iGlarLixi versus BIAsp 30. The two primary objectives of this study were to demonstrate that, compared with BIAsp 30, iGlarLixi was non-inferior in terms of HbA1 c reduction or superior in terms of bodyweight change from baseline to week 26.1

Secondary endpoints

Key secondary efficacy endpoints were assessed at week 26, including HbA1c <7% without weight gain at week 26, HbA1c <7% without weight gain at week 26 and without hypoglycaemia (plasma glucose <3.9mmol/L) during the treatment period, and the superiority of iGlarLixi versus BIAsp 30 in terms of HbA1c reduction from baseline to week 26.1

Other secondary exploratory glycaemic endpoints included the proportion of patients reaching HbA1c target <7% at week 26, HbA1c target <7% without American Diabetes Association (ADA) level 2 hypoglycaemia (<3mmol/L), HbA1c <7 % without weight gain of >1kg, and HbA1c <6.5 %. Other secondary endpoints included change in total insulin dose and change in fasting plasma glucose (FPG), from baseline to week 26.1

Safety endpoints

Safety endpoints were hypoglycaemia, adverse events (AEs), serious AEs (SAEs), AEs leading to treatment discontinuation and AEs leading to death. Hypoglycaemia was defined as: level 1 (<3.9 mmol/L and ≥3mmol/L]), level 2 or level 3 (severe hypoglycaemia), according to the ADA classification. Nocturnal hypoglycaemia was also assessed post-hoc using two definitions: between bedtime and waking, and between 00h00-06h00.1

Box 1: When should treatment be intensified?

The majority of guidelines recommend a glycaemic target of <7% for non-pregnant adult patients. Suboptimal glycaemic control is defined as HbA1c >7%.2

The 2021 ADA guideline recommends that treatment intensification for patients not meeting treatment goals should not be delayed. The early introduction of insulin (a GLP-1RA is preferred to insulin when possible) should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycaemia are present, or when HbA1C levels are >10% or blood glucose levels are >16.7mmol/L.5

If basal insulin has been titrated to an acceptable fasting blood glucose level (or if the dose is >0.5 units/kg/day with indications of need for other therapy) and HbA1c remains above target, consider an FRC.5

A patient-centred approach should be used to guide the choice of pharmacologic agents. Considerations include effect on cardiovascular (CV) and renal comorbidities, efficacy, hypoglycaemia risk, impact on weight, cost, risk for side effects, and patient preferences.5

Among patients with T2DM who have established atherosclerotic CVD disease or indicators of high risk, established kidney disease, or heart failure, a SGLT2i or GLP1-RA with demonstrated CVD benefit is recommended as part of the glucoselowering regimen independent of HbA1C and in consideration of patient-specific factors.5

The treatment programme should be reevaluated at regular intervals (every three to six months) and adjusted as needed to incorporate specific factors that impact choice of treatment.5

Study method

iGlarLixi was injected before a meal using a prefilled disposable pen injector. BIAsp 30 was administered subcutaneously twice daily in the morning and before dinner. Participants were switched from their prior basal insulins at randomisation. OADs were continued without adjustment.1

Starting doses of iGlarLixi were based on prior basal insulin doses, according to labelling instructions. If the previous basal insulin dose at randomisation was <30U, the starting dose was 20 dose steps (20U iGlar, 10μg Lixi) administered with the 10-40U pen (2U:1μg ratio). If basal insulin was ≥30-≤50U, the starting dose was 30 dose steps (30U iGlar, 10μg Lixi) administered with the 30-60U pen (3U:1μg ratio).1

Starting total daily doses of BIAsp 30 were the same as the participants’ previous basal insulin dose on a unit-to-unit basis and split into two daily doses. Doses of iGlarLixi and BIAsp 30 were recommended for weekly titration based on fasting or premeal self-measured plasma glucose, respectively, to a target of 4.4–6.1mmol/L.1

Rescue therapy use was recommended according to the investigator’s clinical judgment for both arms to correct hyperglycaemia persisting beyond prespecified thresholds (HbA1c >8% or FPG >200mg/dL from week 12).1

Rescue therapy was to be considered in the iGlarLixi group when the maximal dose of 60 dose steps was reached. The use of any additional antihyperglycemic treatment (basal insulin, rapid-acting insulin, third daily injection of premix, or OADs) administered to participants in either group with the objective of rescue was included in the analysis of the proportion of participants requiring rescue therapy.1

Overall, participants received treatment with iGlarLixi or BIAsp 30 for a mean duration of 184 or 181 days, respectively. A total of 96.6% in the iGlarLixi group completed the 26-week treatment period and 93.7% in the BIAsp 30 arm.1

What did the SoliMix study find?

Efficacy endpoints

The two primary efficacy endpoints and all three key secondary efficacy endpoints were met. Mean per cent change from baseline to endpoint HbA1 c was 8.6 ± 0.7 % in the iGlarLixi group and 8.6 ± 0.7% in the BIAsp 30 group. At week 26, HbA1 c had improved to 7.3 ± 1.1% in the iGlarLixi group and to 7.5 ±1% in the BIAsp 30 group.1

Statistical noninferiority (margin 0.3 %) of iGlarLixi over BIAsp 30 was demonstrated for the change in HbA1c from baseline to week 26 versus BIAsp 30 was -0.2%.1

Additionally, statistical superiority in HbA1c reduction from baseline to week 26 of iGlarLixi over BIAsp 30 was demonstrated as part of the key secondary endpoint analysis, on the basis of the hierarchical testing procedure.1

At baseline, mean bodyweight was 80.7 ± 16.5kg in the iGlarLixi group and 82.2 ± 18.5kg in the BIAsp 30 group. From baseline to week 26, mean bodyweight decreased to 80.2 ± 16.6kg for iGlarLixi and increased to 83.4 ± 19.0kg for BIAsp 30. Statistical superiority of iGlarLixi over BIAsp 30 was demonstrated for the change in bodyweight from baseline to week 26 (mean -1.9kg).1

Key secondary efficacy endpoints showed that, compared with the BIAsp 30 group, a significantly greater proportion of participants in the iGlarLixi group reached HbA1c <7% without weight gain at week 26, and without weight gain at week 26 and without hypoglycaemia (<3.9mmol/L) during the treatment period.1

The percentage of participants who reached HbA1 c target <7% was higher in the iGlarLixi group than in the BIAsp 30 group. iGlarLixi also demonstrated higher proportions of HbA1c <7% target achievement without ADA level 2 hypoglycaemia, HbA1c <7% without weight gain of >1kg, and HbA1c <6.5% than BIAsp 30.1

Mean FPG at baseline was 8.4 ± 2.4mmol/L in the iGlarLixi group and 8.3 ± 2.3mmol/L in the BIAsp 30 group. At week 26, mean FPG was 7.2 ± 2.4mmol/L in the iGlarLixi group and 8.1 ± 2.8 mmol/L in the BIAsp 30 group. The difference between groups in change from baseline to week 26 was -0.9mmol/L.1

After 26 weeks, the increase in mean total daily insulin dose was smaller in the iGlarLixi group than in the BIAsp 30. The percentage of participants who required rescue therapy was low and similar for iGlarLixi (1.8%) and BIAsp 30 (2.3%).1

Safety profile

The proportion of participants with at least one hypoglycaemic event was lower in the iGlarLixi group compared with the BIAsp 30 group (0.62). Lower incidence of hypoglycaemia with iGlarLixi versus BIAsp 30 was also observed across level 1 and 2 hypoglycaemia categories.1

Rates of hypoglycaemia followed the same pattern as incidence. There was an overall lower rate of any hypoglycaemia with iGlarLixi compared with BIAsp 30, as well as lower rates of level 1 and 2 hypoglycemia.1

Three severe hypoglycaemic episodes (level 3) were reported: one occurred in the iGlarLixi group and two in the BIAsp 30 group. In addition, lower incidence (0.37) and event rates (0.28) of level 2 nocturnal hypoglycaemia were observed in the iGlarLixi group versus the BIAsp 30 group.1

Similar patterns were seen when using the between 00h00-06h00 definition: lower incidence (0.32) and event rates (0.30) were seen with iGlarLixi versus BIAsp 30.1

During the 26-week randomised treatment period, the percentage of participants who had at least one AE was slightly higher in the iGlarLixi group (32.6%) compared with the BIAsp 30 group (27.7%), the difference being mainly due to the higher incidence of GI events in the iGlarLixi group (10.4% vs 2.3%). A large proportion of these GI events were reported in the first week of treatment.1

The most commonly reported AE in the iGlarLixi group was nausea (7.7% vs 0% for BIAsp 30), while nasopharyngitis was the most commonly reported AE in the BIAsp 30 group (2.7% vs 3.2% for iGlarLixi). In both treatment groups, the majority of participants had AEs considered mild or moderate in severity.1

SAEs were reported by a similar proportion of participants in both treatment groups (2.7% iGlarLixi and 2.9% BIAsp 30). Overall, the rate of study discontinuation due to an AE was low and similar in both treatment groups (0.9%). There were two fatal AEs (acute coronary syndrome and cardiac failure/pulmonary oedema) during the study period, both in the BIAsp 30 group. Neither of these fatal AEs were considered related to study treatment.1

Box 2: What is iGlarLixi?

iGlarLixi combines two different glucoselowering agents with complementary mechanisms of action. Insulin glargine is a long-acting basal insulin that targets FPG levels by mimicking physiologic insulin secretion to provide peakless insulin levels over a 24-hour period.1,4

Lixisenatide is a once-daily GLP-1RA that increases insulin levels and decreases glucagon secretion in a glucose-dependent manner, minimising the risk of treatment-related hypoglycaemia. Lixisenatide also slows gastric emptying, which reduces the rate at which postmeal glucose enters the circulation, thereby diminishing PPG excursions.4

Lixisenatide was approved by the American Food and Drug Administration in 2016 as an adjunct to diet and exercise for treatment of patients with T2DM.4

In recommendations from ADA and the European Association for the Study of Diabetes, a GLP-1RA can be used early in treatment or as intensification of basal insulin therapy to provide additional prandial control, or basal insulin can be added to existing GLP-1 receptor agonist therapy as part of a stepwise approach (see box 2).4

In addition, the use of initial combination therapy with agents that correct specific pathophysiologic disturbances and that have complementary mechanisms of action support the pathophysiologic approach for the management of T2DM.4

The development of the FRC of insulin glargine and lixisenatide follows a patientcentric treatment approach, since iGlarLixi provides several advantages over administering its component treatments separately.4

iGlarLixi offers simpler and more convenient treatment initiation, dosing schedules, and titration for healthcare professionals and patients. Furthermore, the combination mitigates the weight gain associated with insulin alone and is better tolerated than lixisenatide alone because of the relatively slow increase in GLP-1RA dose in the FRC.4

This slower increase of GLP-1 receptor agonist dose reduces the risk of GI AEs such as vomiting, nausea and diarrhoea typically associated with GLP-1RAs.4

A simplified regimen may improve adherence by reducing the number of injections required compared with administering the components separately. Studies have shown that adherence decreases as treatment regimens become more complicated and more injections are added.4

Furthermore, the expected reduction in GI adverse events, a reduced risk of hypoglycaemia, and weight neutrality are likely to have positive impacts on treatment adherence.4

Conclusion

Once-daily iGlarLixi provided better glycaemic control with weight benefit and less hypoglycaemia than twice-daily premix BIAsp 30. iGlarLixi is a more efficacious, simpler, and well-tolerated alternative to premix BIAsp 30 in suboptimally controlled T2DM diabetes requiring treatment beyond basal insulin plus OAD therapy.1

References

1. Rosenstock J, Emral R, Sauque-Reyna L, et al. Advancing therapy in suboptimally controlled basal insulin-treated type 2 diabetes: Clinical outcomes with iGlarLixi versus premix BIAsp 30 in the SoliMix randomized controlled trial. Diabetes Care, 2021.

2. Khunti K, Damci T, Husemoen LL. Exploring the characteristics of suboptimally controlled patients after 24 weeks of basal insulin treatment: An individualized approach to intensification. Diabetes Research and Clinical Care, 2017.

3. De Kok A. Advancing therapy in suboptimally controlled basal insulin-treated type 2 diabetes: The SoliMix trial. Sanofi, July, 2021.

4. Hinnen D and Strong J. iGlarLixi: A New Once-Daily Fixed-Ratio Combination of Basal Insulin Glargine and Lixisenatide for the Management of Type 2 Diabetes. Spectrum Diabetes Journal, 2018.

5. ADA. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2021. Diabetes Care, 2021. SF

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