Introduction
Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder marked by persistently high blood glucose levels. This occurs due to insulin resistance coupled with dysfunction of both alpha- and beta-cells. Prolonged periods of poor glycemic control can lead to blood vessel damage, causing organ failure and dysfunction, impacting the heart, brain, kidneys, retina, and lower limbs. Diabetes is a prevalent chronic disease in Canada, with T2DM accounting for 90% of cases. In 2015, an estimated 3.4 million Canadians (9.3% of the population) were living with diabetes, and projections suggest this number will rise to 5 million (12.1% of the population) by 2025. These statistics highlight the significant economic burden of diabetes in Canada.
As T2DM advances, insulin production decreases, often necessitating the use of exogenous insulin, such as insulin glargine, to manage blood glucose levels. While insulin is a cornerstone in T2DM treatment, its use can lead to side effects like hypoglycemia and weight gain. Glucagon-like peptide-1 (GLP-1) analogues, such as lixisenatide, are effective glucose-lowering agents that mimic the effects of endogenous GLP-1. They stimulate insulin release when blood glucose is high, reducing both fasting and post-prandial glucose levels. These actions also decrease gastric emptying and promote satiety, potentially aiding in weight management. However, GLP-1 analogues can cause gastrointestinal side effects, including nausea, diarrhea, and vomiting.
Soliqua is a fixed-ratio combination (iGlarLixi) of basal insulin glargine and the GLP-1 analogue lixisenatide, administered via a once-daily injection. Health Canada has approved iGlarLixi as an adjunct to diet and exercise for improving glycemic control in adults with T2DM who are not adequately controlled on basal insulin (less than 60 units daily), either alone or with metformin. It is available in a pen-injector containing 100 units/mL insulin glargine and 33 mcg/mL lixisenatide at a 3:1 ratio, allowing for daily doses of 15 to 60 units of insulin glargine and 5 to 20 mcg of lixisenatide. This review aims to systematically evaluate the benefits and risks of iGlarLixi in treating adults with T2DM inadequately controlled on basal insulin, with or without metformin.
Overview of Soliqua 100/33
Soliqua 100/33 is a brand-name injection pen containing a fixed-dose combination of insulin glargine and lixisenatide used to treat type 2 diabetes in adults alongside diet and exercise. It works through the combined action of these two medications. Insulin glargine is a biosynthetic human insulin analog produced using genetic engineering technology. It resembles human insulin in structure but has modified amino acids to allow for slow release from the injection site. Lixisenatide mimics the actions of GLP-1, a naturally occurring hormone that regulates blood glucose levels. It stimulates insulin secretion and lowers glucagon secretion when blood glucose levels are high, also slowing down the rate at which the stomach empties.
Soliqua 100/33 is available as a fixed-dose combination of insulin glargine 100 units/mL and lixisenatide 33 mcg/mL. The insulin glargine in Soliqua forms microprecipitates when injected subcutaneously, allowing for slow release. The pen delivers doses from 15 to 60 units in a single injection, with a maximum daily dose of 60 units (equating to 60 units of insulin glargine and 20 mcg of lixisenatide). The recommended starting dose is 15 units/day for those on < 30 units of basal insulin daily or 30 units/day for those on 30-60 units of basal insulin/day.
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LixiLan-L Study: Efficacy and Safety of iGlarLixi
The CADTH systematic review included one multi-center, parallel-group, open-label, randomized controlled superiority study. The LixiLan-L trial (N = 736) was a pivotal 30-week, active-controlled trial assessing the efficacy and safety of iGlarLixi in adult patients with T2DM inadequately controlled on basal insulin, with or without metformin. Participants were randomized (1:1) to iGlarLixi (N = 367) or insulin glargine (N = 369). The primary efficacy outcome was the mean change from baseline in glycated hemoglobin (A1C) at week 30. Secondary efficacy endpoints included changes in body weight, fasting plasma glucose, and two-hour glucose excursion. Exploratory outcomes included the proportions of patients achieving A1C < 7% and ≤ 6.5%, changes in health-related quality of life measures (EuroQol 5-Dimensions [EQ-5D] and Impact of Weight on Quality of Life-Lite [IWQoL-Lite] questionnaires), and changes in two-hour post-prandial plasma glucose over time. Safety outcomes included mortality, treatment-emergent adverse events (AEs), serious AEs, withdrawals due to AEs, and notable harms like hypoglycemia, immunogenicity, and pancreatitis.
Limitations of the LixiLan-L Study
Several limitations were noted in the LixiLan-L study. The open-label design increases the potential for bias in reporting subjective outcomes, such as AEs and health-related quality of life. Outcomes of interest, including two-hour post-prandial plasma glucose, health-related quality of life measures, hypoglycemic events, and the proportion of patients achieving A1C < 7% or ≤ 6.5%, were not appropriately adjusted for multiplicity, increasing the risk of type I error. The insulin glargine dose was capped at 60 units to match the maximum allowable dose in iGlarLixi, raising concerns about the impact of this capped dose on the clinical generalizability of the results. Finally, the 30-week duration limits the ability to detect changes in more clinically important outcomes, such as cardiovascular-related outcomes and mortality.
Efficacy Results
At week 30, the iGlarLixi group showed a greater reduction in A1C from baseline (−1.13%; SD 0.057%) compared to the insulin glargine group (−0.62%; SD 0.055%), achieving a mean A1C value of 6.94% (SD 0.87%) versus 7.48% (SD 0.91%) in the insulin glargine group. The difference between the two groups was −0.52% (95% CI, −0.633% to −0.397%) in favor of iGlarLixi, which was statistically significant (P < 0.0001). The clinical expert considered this difference clinically relevant over a duration where a meaningful change would be expected. A numerically higher proportion of patients in the iGlarLixi group achieved an A1C less than 7.0% at week 30 (54.9% versus 29.6% in the insulin glargine group), with similar results for those achieving an A1C equal to or less than 6.5% (33.9% versus 14.2%). These results should be considered exploratory due to the lack of adjustment for multiplicity.
Patients treated with iGlarLixi also experienced a statistically significantly greater reduction in two-hour plasma excursion (LSMD −3.43 mmol/L; 95% CI, −3.925 mmol/L to −2.939 mmol/L; P < 0.0001). Change in two-hour post-prandial plasma glucose from baseline to week 30 was not part of the statistical testing hierarchy and should be considered exploratory.
No significant difference was observed between the groups in the change in fasting plasma glucose from baseline to week 30 (adjusted mean difference 0.11 mmol/L; 95% CI, −0.207 mmol/L to 0.428 mmol/L; P = 0.4951), but these results should be considered exploratory.
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Mean body weight decreased in the iGlarLixi group (−0.67 kg; SE 0.181 kg) and increased in the insulin glargine group (+0.70 kg; SE 0.178 kg). There was a statistically significant difference between groups for change in mean body weight from baseline to week 30 (adjusted LSMD −1.37 kg; 95% CI, −1.808 kg to −0.930 kg, P < 0.0001).
Harms
The percentage of patients reporting any treatment-emergent adverse reactions was similar in the iGlarLixi (53.4%) and insulin glargine (52.3%) groups. The percentage of patients with serious AEs was also similar (5.5% versus 4.9%, respectively). The most frequently reported treatment-emergent AEs that occurred more frequently in the iGlarLixi group were nausea (10.4% compared with 0.5%), headache (5.8% compared with 2.7%), diarrhea (4.4% compared with 2.7%), and vomiting (3.6% compared with 0.5%). The rate of withdrawals due to AEs was low in both groups (< 3%), but higher in the iGlarLixi group (2.7%) than in the insulin glargine group (0.8%), with nausea being the most common reason for withdrawal in the iGlarLixi group (1.1%). There were three deaths during the trial: one in the iGlarLixi group (pneumonia) and two in the insulin glargine group (cardiopulmonary failure and gallbladder cancer).
The frequency of patients experiencing at least one documented symptomatic hypoglycemia event (plasma glucose concentration ≤ 3.9 mmol/L) was 40.0% for iGlarLixi and 42.5% for insulin glargine. The occurrence of severe hypoglycemia was numerically higher in the iGlarLixi group (1.1% versus 0.3% in the insulin glargine group).
Allergic reactions were low in frequency and similar between groups (0 in the iGlarLixi group versus 0.3% in the insulin glargine group). There was no documented occurrence of pancreatitis.
Indirect Treatment Comparisons
Two indirect treatment comparisons were reviewed: one submitted by the manufacturer and one found through a CADTH Common Drug Review literature search. The manufacturer-submitted indirect comparison (IDC) compared the efficacy of iGlarLixi with currently available regimens for T2DM, focusing on glycemic control, weight changes, and risk of hypoglycemic events. The only comparison that consistently showed a favorable result compared with iGlarLixi was basal insulin (once daily) + one oral antidiabetes drug. iGlarLixi was also found to be potentially better at reducing weight gain compared with insulin regimens and DPP-4 inhibitors in conjunction with basal insulin, but not when compared with GLP-1 receptor agonists in conjunction with basal insulin (except albiglutide). iGlarLixi showed a favorable hypoglycemic profile against basal insulin regimens alone and against GLP-1 receptor agonists in conjunction with basal insulin, although results were not available for comparisons with insulin degludec/liraglutide (iDegLira), liraglutide, dulaglutide, or any DPP-4 inhibitor.
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The IDC found in the literature (Evans et al. 2018) examined phase III trials comparing iGlarLixi and iDegLira in insulin-experienced patients. iDegLira was found to be better than iGlarLixi at reducing A1C from baseline and reducing weight.
Both IDCs have limitations, reducing the overall certainty in the results. The manufacturer’s IDC is not up to date and is missing evidence published within the last two years, while the literature-identified IDC did not follow a systematic review approach and included only pivotal trials of various diabetes interventions.
SoliMix Study: iGlarLixi vs. Premixed Insulin
The SoliMix study was a 26-week, randomized controlled trial involving 887 adults with type 2 diabetes uncontrolled on insulin plus metformin with or without a sodium-glucose cotransporter-2 inhibitor (SGLT-2i). It compared Soliqua 100/33 to a commonly used premixed insulin (biphasic insulin aspart 30, BIAsp 30). Participants were randomized to switch to either Soliqua 100/33 once daily or premixed insulin twice daily, with doses adjusted weekly.
The study met its two primary endpoints, with Soliqua 100/33 demonstrating noninferiority in blood sugar (HbA1c) reduction and superiority in body weight change from baseline compared to premixed insulin. Safety findings were consistent with the established profiles of both treatments.
Potential Place in Therapy
Approximately 40% of patients with T2DM treated with basal insulin, with or without other oral antidiabetes drugs, do not achieve A1C targets and require additional therapy. Adding prandial insulin one to three times daily has been a traditional approach, but this increases complexity, the number of injections, and is associated with weight gain and hypoglycemia. There is an unmet need for a simple and convenient therapy that will not increase hypoglycemia and will provide a weight benefit. GLP-1 receptor analogues are ideal drugs to combine with basal insulin due to their simple titration regimens, improvement in A1C and post-prandial plasma glucose, without increasing hypoglycemia, and weight-loss benefits.
Fixed-ratio combinations of basal insulin with GLP-1 analogues allow for combining these two classes in a single injection. iGlarLixi has been studied in patients with T2DM suboptimally controlled on basal insulin, with or without up to two oral drugs, in the LixiLan-L trial. Titrated iGlarLixi compared with insulin glargine significantly improved A1C and lowered body weight without increasing hypoglycemia. iGlarLixi was well tolerated, with lower rates of gastrointestinal adverse effects than other lixisenatide trials, likely due to the slow titration during the trial.
The trial data with iGlarLixi support using this drug in patients with an elevated A1C despite therapy with basal insulin, with or without metformin or other oral drugs. It also adds the convenience of a single injection with two drugs, rather than separate injections of basal insulin and a GLP-1 analogue. It may be particularly useful for patients with good fasting glucose control on basal insulin, but elevation in A1C and post-prandial hyperglycemia, especially after the largest daily meal. The weight benefit versus insulin alone is also important, given that about 85% of individuals with T2DM are overweight or obese.
iGlarLixi provides a novel way to combine a GLP-1 analogue with basal insulin in a convenient single injection for individuals with elevated A1C despite therapy with basal insulin. Its use in practice will be consistent with Diabetes Canada 2018 guidelines that recommend “a GLP-1 receptor analogue be considered as add-on therapy to basal insulin before initiating bolus insulin or intensifying insulin to improve glycemic control with weight loss and a lower hypoglycemia risk compared with single or multiple bolus insulin injections.”
Weight Management with Soliqua
Weight gain is not a common side effect of Soliqua (insulin glargine and lixisenatide). In some clinical studies, patients using Soliqua had an average weight loss of 0.1 and 0.3 kg (0.2 and 0.7 lb). The average body weight decreased by 0.7 kg (1.5 lbs) with insulin glargine/lixisenatide but increased by 0.7 kg (1.5 lbs) in patients using insulin glargine only. Insulin can lead to weight gain, while GLP-1 agonists are known to cause weight loss. In the LixiLan-L trial, mean body weight from baseline to week 30 decreased in the iGlarLixi group (−0.67 kg) and increased in the insulin glargine group (+0.70 kg), with a statistically significant difference between groups (adjusted LSMD −1.37 kg; P < 0.0001).
Side Effects of Soliqua 100/33
Soliqua 100/33 can cause side effects, some of which are more common than others. These side effects may be temporary, lasting a few days to weeks. Common side effects reported in clinical trials include:
- Upper respiratory infections, such as the common cold
- Runny or stuffy nose
- Low blood sugar
- Headache
- Problems with digestion, such as nausea or diarrhea
Serious side effects that have been reported include:
- Hypokalemia (low potassium level)
- Sudden kidney injury
- Pancreatitis
- Gallstones and cholecystitis (inflammation in your gallbladder)
- Severe low blood sugar
- Allergic reactions
Managing Side Effects
- Low Blood Sugar (Hypoglycemia): Monitor blood sugar levels regularly, especially when starting Soliqua 100/33 or changing dosages. Be aware of symptoms such as headache, shaking, sweating, confusion, and dizziness. Carry a source of fast-acting carbohydrates to treat low blood sugar episodes.
- Headache: If headaches occur, consider over-the-counter pain relievers like acetaminophen (Tylenol).
- Problems with Digestion: These side effects are more likely to occur when first starting Soliqua 100/33 and generally subside as the body adjusts. Stay hydrated by drinking fluids like Pedialyte or Gatorade if experiencing diarrhea or vomiting.
- Injection Site Reactions: Rotate injection sites each time you administer Soliqua 100/33 to help lower your risk of injection site reactions. You can inject Soliqua 100/33 into your thigh, abdomen, or upper arm.
Important Considerations
- Allergic Reactions: Seek immediate medical care if you experience symptoms of a severe allergic reaction, such as swelling or trouble breathing.
- Kidney Problems: Soliqua 100/33 may not be suitable for individuals with kidney conditions.
- Liver Problems: The dosage of Soliqua may need to be reduced for liver disease.
- Heart Failure: Taking certain diabetes pills called TZDs (thiazolidinediones) with Soliqua 100/33 may cause heart failure in some people.
- Pregnancy and Breastfeeding: Lixisenatide may pose a risk to the fetus in pregnant women; therefore, it should only be used in pregnancy if the benefits outweigh the risks. There is not enough data about the risks of taking lixisenatide during breastfeeding, so Soliqua should only be used if the benefits justify the risks.
- Drug Interactions: Soliqua 100/33 may interact with other medications, affecting their absorption or increasing the risk of side effects. Consult with your doctor about all medications you are taking.