Is There a Role for Fixed-Ratio Injectable Combinations in Type 2 Diabetes?

Pharmacotherapy for diabetes management has expanded in recent years with several new drug classes. Beyond lowering A_1c, some medications show promise for reducing cardiovascular risk.^1-2 Current guidelines recommend several options for patients who have not reached their goal A1c on metformin monotherapy including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or basal insulin.³  However, if basal insulin is chosen as the first add-on treatment with metformin, the post-prandial blood glucose (PPG) often will remain elevated.  A combination product that includes both a basal insulin plus a GLP-1 RA has the potential to addresses both fasting blood glucose and PPG … and perhaps has some other advantages over using either product alone.  Two fixed-dose ratio combination products containing basal insulin and GLP-1 RAs have recently been approved by the FDA:  Insulin glargine/lixisenatide (Soliqua^TM or iGlarLixi) and insulin degulec/liraglutide (Xultophy^® or iDegLira).

The Lixilan-O trial was an open-label, randomized, parallel-group, multi-national, multi-center phase III trial evaluating the combination of insulin glargine (iGlar) and lixisenatide (Lixi) compared to iGlar or Lixi alone in patients on oral therapy.⁴ Efficacy outcomes included change in A_1c (primary), 2-h PPG, fasting plasma glucose (FPG), seven-point self-measured plasma glucose (SMPG), and body weight. Safety outcomes included symptomatic hypoglycemia and adverse events. Patients with type 2 diabetes on metformin with or without a second oral agent, an A_1c between 7.0 and 10.0%, and a FPG ≤ 250 mg/dl were eligible for this study. Patients were excluded if they had previously taken insulin or a GLP-1 RA. Doses of iGlar and iGlarLixi were titrated weekly to a goal FPG between 80 and 100 mg/dl unless the patient experienced hypoglycemia. Patients receiving Lixi monotherapy were started on 10 µg/day and titrated to 20 µg/day after 2 weeks. iGlarLixi can deliver a maximum dose of 60 units/day of iGlar and 20 µg/day of Lixi in two fixed-dose ratio pens.

The study enrolled 1170 patients who were randomly assigned to iGlarLixi (n=469), iGlar (n=467), or Lixi (n=234). Baseline patient characteristics were similar among groups. The average patient was middle aged (58 years old) with diabetes for 8.8 years.  A slight majority (51%) were male and over 90% were Caucasian.  The mean baseline A_1c was 8.1%. The majority of patients were obese with a mean baseline BMI 32 kg/m². Over half of patients were previously treated with a sulfonylurea; however, all agents except metformin were discontinued prior to a 4-week run-in phase.

After 30 weeks, iGlarLixi demonstrated superiority over Lixi and iGlar in terms of mean A_1c reduction.  See Table 1. Additionally, significant benefit was seen in the iGlarLixi group for several secondary endpoints including proportion of patients reaching target A_1c of <7% and ≤6.5%.  As expected, patients in the iGlar group experienced weight gain while those in the iGlarLixi and Lixi groups experienced weight loss. FPG was similar between iGlar and iGlarLixi groups and the 2-h PPG was similar between Lixi and iGlarLixi groups.

In terms of safety, hypoglycemia was similar between iGlarLixi and iGlar groups, but lower in the Lixi group. Treatment with iGlarLixi (21.7%) led to fewer gastrointestinal effects than Lixi (36.9%).

Table 1 – LixiLan-O Study Outcomes

^{NR = not report, per protocol using a step-down testing procedure.}

Translating the results of the trial to clinical practice is hampered by a few limitations. The vast majority of patients were Caucasian – thus it is unknown how high-risk minority groups would respond to the iGlarLixi combinaton. Additionally, the study was open-label – so the clinicians (or patients) may have behaved differently depending on which treatment group the patient was assigned.  Many patients were on dual oral therapy before entering the trial, but all drugs were stopped other than metformin. In clinical practice, oral agents are often continued. Thus it is unclear what the benefits of iGlarLixi might be in patients who are naive to alternative therapies or who continue other oral therapies in addition to metformin.

Although a large percentage of patients that achieved A_1c goals, the mean baseline A_1c was only 8.1% – so this treatment approach might not achieve the same outcomes in patients with a higher A_1c.  Importantly, this trial does not provide any data regarding iGlarLixi use in patients with an A_1c great than 10% – a population that was excluded.  Given that the iGlarLixi product has a maxiumum insulin glargine dose of 50 units, it might be difficult to get to goal in those with a very elevated A_1c. Noteably, 16% of patients in iGlarLixi group were titrated to the maximum daily dose.

The results of the Lixilan-O trial are not surprising.  One would expect greater A_1c lowering when adding two agents versus a single add-on treatment.  However, this combination may have a significant impact on clinical practice. First, the results indicate that patients not yet at goal on metformin monotherapy benefit from a step-up to triple therapy.  Although guidelines currently recommend a step-wise addition of agents to lower A_1c, clinical inertia — the reluctance to make changes in a therapeutic treatment plan — often leads to suboptimal care for patients.⁵ This notion of aggressive treatment is supported by previous literature urging early intervention with multi-drug therapy in order to preserve beta-cell function and decrease insulin resistance.⁶ Second, there may be a benefit to controlling postprandial blood glucose because it may reduce the risk for cardiovascular complications, further supporting initiation of a GLP-1 RA.⁷ Third, medication adherence may improve when combination products are used.⁸

Patients can only benefit from therapy if they actually take it. The combination of two injectable medications may offer improved adherence by reducing injection burden. Patient satisfaction may also be improved as the combination of iGlarLixi offers fewer injections per day when compared to daily basal-bolus insulin regimens or basal insulin plus GLP-1 RA regimens. Admittedly, adherence and patient satisfaction were not evaluated in this study.

An encouraging finding in this study is the mitigation of weight gain when initiating a GLP-1 RA with insulin therapy.  Weight gain can be discouraging to patients and contributes to further insulin resistance as well as higher insulin doses.

Nausea and other gastrointestinal (GI) side effects often limits the use of GLP-1 RAs. The combination product allows for a more gradual titration of the GLP-1 RA dose and this may explain the lower incidence of GI side effects observed in this study. Again, this supports patient adherence and satisfaction.  However, iGlarLixi must be administered prior to meals which may be difficult for some patients. The alternative combination injectable product, iDegLira, does not have this limitation.

The Lixilan-O trial provides compelling evidence regarding a novel, aggressive, and safe treatment option for patients needing further glycemic control on metformin monotherapy. A similar trial, Lixilan-L, compared iGlarLixi to iGlar in patients previously treated with basal insulin and demonstrated similar results.⁹ The benefits of iGlarLixi and iDegLira (weight neutral, lower risk of hypoglycemia, lower incidence of nausea) should outweigh concerns related to their cost and fixed-ratio. What do you think?  Are these combination products the ideal add-on when metformin isn’t enough?