A long-acting insulin for adults with type 1 or type 2 diabetes.

Key points

  • Long-acting insulin for adults with type 1 and 2 diabetes
    Insulin glargine 300 IU/mL solution (Gla-300) is a basal insulin, administered subcutaneously once daily. It is approved only for use in patients aged ≥ 18 years.
  • Similar efficacy and safety to that of insulin glargine 100 IU/mL solution (Gla-100)
    Gla-300 is a concentrated formulation of the already PBS-listed Gla-100. Over 6 months Gla-300 provided similar glycaemic control and had comparable rates of adverse events to those for Gla-100.
  • Similar to, but not interchangeable with, Gla-100
    Dose adjustments and close monitoring are required when switching from one formulation to the other.
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Evidence Snapshot

What is known about this medicine? 

Gla-300 is a long-acting basal insulin for the treatment of type 1 and 2 diabetes in adults. It is administered subcutaneously once daily via a disposable prefilled injector pen.

Gla-300 is a concentrated form of Gla-100, also listed on the PBS. It has a similar efficacy and tolerability profile to that of Gla-100 in the treatment of type 1 and type 2 diabetes.

Areas of uncertainty

Safety data for this formulation have not been collected beyond 12 months.

In clinical trials, hypoglycaemia was generally less frequent with Gla-300 than with Gla-100 in patients with type 2 diabetes, including in the predefined study secondary endpoint, which reported on nocturnal hypoglycaemia (confirmed and/or severe events). This difference was not statistically significant in all studies.

A slightly higher dose of Gla-300 compared with Gla-100 was required by the end of the 6-month treatment period in all pivotal trials. The cause of this is unclear but is proposed to be due to a slight decrease in the bioavailability of Gla-300.

What does NPS MedicineWise say?

Gla-300 is another option for adults with type 1 or type 2 diabetes requiring a long-acting basal insulin. It may be convenient for patients who require a higher dose of insulin, as each pen will last longer than a basal insulin pen with fewer units of insulin.

As is standard with insulin therapy, adjust dose of Gla-300 on an individual basis. Dose adjustment is likely to be needed when switching from Gla-100; Gla-300 and Gla-100 are not interchangeable.

Consult guidelines about starting or switching basal insulin regimens, and combining treatment with short- or rapid-acting insulin and oral diabetes medicines. Take precautions as needed for other basal insulins.

PBS listing

Unrestricted benefits

Gla-300 has an Unrestricted benefits listing on the Pharmaceutical Benefits Scheme (PBS);1,2 however, it is approved by the Therapeutic Goods Administration (TGA) for the treatment of diabetes mellitus in adults only.3,4

May be prescribed by nurse practitioners

Authorised nurse practitioners may prescribe this medicine on the PBS. 

See the PBS website for more information on nurse practitioner PBS prescribing

What is it? 

Gla-300 is a long-acting human insulin analogue administered subcutaneously, once daily.5,6 It is packaged in a disposable prefilled injector pen containing 450 IU of insulin glargine in 1.5 mL of solution.5

Gla-300 is a concentrated formulation of the already PBS-subsidised Gla-100. According to a pharmacokinetics and pharmacodynamics study, Gla-300 has a slightly different activity profile to that of Gla-100, which may result in a more constant glucose-lowering effect over 24 hours.7

Who is it for? 

Gla-300 is an alternative basal insulin for adults with type 1 or type 2 diabetes requiring long-acting insulin.

Convenient for patients requiring high-dose insulin

The increased number of units of insulin per injection pen may be convenient for patients who require a large dose of insulin, as a single pen contains more doses.

The increased number of units of insulin, coupled with the same shelf life for opened products as other insulins (28 days), may result in wastage in a small group of patients taking less than 16 units daily.

For use by patients aged ≥ 18 years

Gla-300 is TGA-approved for use by patients aged ≥ 18 years only; safety and efficacy have not been established in patients under 18 years.3

Where does it fit? 

Gla-300 joins Gla-100 and detemir on the list of long-acting basal insulins currently available in Australia. Unlike the insulin glargine formulations that have an Unrestricted benefits listing on the PBS, detemir is only available on the PBS for patients with type 1 diabetes.8,9

Type 1 diabetes: first-line therapy

An insulin regimen consisting of basal insulin plus mealtime bolus insulin is recommended as a first-line treatment for patients with type 1 diabetes.10 A long-acting basal insulin (glargine or detemir) is preferred to intermediate-acting insulin (isophane) for the basal component, and a very-short-acting insulin is preferred for the bolus component of treatment.10

Type 2 diabetes: second-line therapy

Patients not meeting glycaemic targets with metformin should have a second diabetes medicine added to their therapy.

Basal insulin is one option for second-line add-on therapy; other options include a sulfonylurea, dipeptidyl-peptidase-4 inhibitor (gliptin), sodium glucose co-transporter 2 (SGLT2) inhibitor, glucagon-like-peptide-1 agonist, thiazolidinedione (glitazone) or acarbose.10-12

National RACGP guidelines on the management of type 2 diabetes in general practice include recommendations about adding on second-line therapy.

How does it compare?

The safety and efficacy of Gla-300 was compared with that of Gla-100 only. There are no data on the comparative efficacy of Gla-300 and other diabetes medicines.

A number of Phase 3 head-to-head clinical trials have been published comparing Gla-300 with Gla-100 in patients with type 1 diabetes13,14 and in patients with type 2 diabetes.15-18 Trials included an initial 6-month treatment period followed by a 6-month extension period.

Patients in all trials were aged 18 years or over, with a baseline HbA1c (glycated haemoglobin) of 53–86 mmol/mol (7–10%) for those with type 1 diabetes, and 53–97 mmol/mol (7–11%) for those with type 2 diabetes.13-18

In all trials, basal insulin was administered once daily.

The dose was generally titrated once weekly and no more than every 3 to 4 days, aiming for a fasting self-monitored plasma glucose target of 4.4–7.2 mmol/L in the type 1 diabetes trials13,14 and 4.4–5.6 mmol/L in the type 2 diabetes trials.15-18 Cessation of titration was left to the individual judgement of the investigators and participants.15

All trials were open label because the two glargine solutions were administered using different injection devices. The potential for biased safety and efficacy outcomes due to lack of blinding cannot be excluded.

Similar efficacy to that of Gla-100 for glycaemic control

Over 12 months Gla-300 provided comparable blood glucose control to that of Gla-100 for people with type 1 diabetes, as measured by HbA1c levels:14

  • mean reduction in HbA1c was 0.20% (2.2 mmol/mol) for Gla-300 and 0.22% (2.4 mmol/mol) for
    Gla-100.

Patient-level meta-analysis of the pivotal Phase 3 trials for people with type 2 diabetes showed that treatment with Gla-300 or Gla-100 over 12 months was associated with:

  • a mean reduction in HbA1c from baseline of 0.91% (–9.95 mmol/mol) for Gla-300 and 0.80 % (–8.74 mmol/mol) for Gla-10018,19 20,21
  • a least squares mean between-group difference (95% CI) from baseline of –0.10 (–0.18 to –0.02)% or −1.09 mmol/mol (95% CI −2.01 to −0.20); p = 0.0174 (Gla-300, n = 1165; Gla-100, n = 1170).

At 12-month follow-up, a slightly higher dose of Gla-300, compared with Gla-100, was needed to maintain similar control of blood sugar levels:

  • type 1 diabetes: 15.6% higher dose13,14
  • type 2 diabetes: 14% higher dose.18,19

The cause of the higher dose requirement might be due to a slight decrease in the bioavailability of Gla-300.15,19 It is speculated that Gla-300 resides in the subcutaneous space longer than Gla-100, which leads to a larger amount of the insulin being inactivated by tissue peptidases at the injection site.15,19

Slight differences in weight gain

Over the initial 6-month trial period, patients with type 1 diabetes who received Gla-300 generally gained slightly less weight (mean increase of 0.5 kg) than those who received Gla-100 (mean increase of 1.0 kg).13,19 This statistically significant difference was lost at 12 months.14

During the 12-month trial period, for people with type 2 diabetes treated with Gla-300, significantly less weight gain was observed compared with those treated with Gla-100 (mean between-group difference –0.40 kg, 95% CI –0.71 to –0.09, p = 0.01).18

Safety issues

The glargine molecule in both the 300 IU and 100 IU formulations is the same, so, as might be anticipated, types and rates of adverse events were similar for both treatment groups.

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Hypoglycaemia

Rates of hypoglycaemic events with Gla-300 and Gla-100 over the initial 6-month trial period were as follows.

  • A similar proportion of patients with type 1 diabetes reported one or more confirmed (≤ 3.9 mmol/L) or severe hypoglycaemic events in both treatment groups; 93% in the Gla-300 group and 94% in the Gla-100 group.13
  • For patients with type 2 diabetes, pooled analysis reported a lower cumulative number of confirmed or severe hypoglycaemic events per participant with Gla-300 compared with Gla-100 at any time of the day. Similar trends were observed when rates were annualised for any time of the day and for nocturnal events only.

For people with type 1 diabetes treated over 12 months, confirmed or severe hypoglycaemic events were similar across both groups, with most participants experiencing one or more nocturnal events (73%, Gla-300; 75%, Gla-100).14

For people with type 2 diabetes treated over 12 months, annualised rates of confirmed or severe hypoglycaemia were comparable between groups for any time of the day (rate ratio 0.97, 95% CI 0.87 to 1.09), but lower for Gla-300 when nocturnal events only were considered (rate ratio 0.82, 95% CI 0.67 to 0.99).18

Severe hypoglycaemic events were defined as those needing assistance by another person to administer therapy.15

  • In the 6-month trial period fewer patients reported severe hypoglycaemia with Gla-300 (6.6%) than with Gla-100 (9.5%).13
  • Similar findings were reported in the 12-month trial period, where 9% of patients treated with Gla-300 and 11% of patients with Gla-100 reported severe hypoglycaemia.14

Other adverse events

Rates of treatment-emergent adverse events (TEAEs) were similar for Gla-300 and Gla-100 for patients with either type 1 or type 2 diabetes.13,14,18,19

Other than hypoglycaemia, injection-site reactions were the most frequently reported TEAEs considered related to the study treatment.16,18

  • For patients with type 2 diabetes, 3% in the Gla-300 group and 3.5% in the Gla-100 group experienced injection site reactions.18,19
  • For patients with type 1 diabetes, the corresponding figures were 2.2% in the Gla-300 group and 1.5% in the Gla-100 group in the 6-month trial period.13 In the 12-month period, 2.9% of participants in the Gla-300 group and 1.5% of participants in the Gla-100 group experienced injection site reactions.14

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended the listing of Gla-300 for the treatment of diabetes mellitus on the basis of cost-minimisation compared with Gla-100.22

The PBAC accepted that Gla-300 is non-inferior in effectiveness to Gla-100 but did not accept that it improved the incidence of hypoglycaemic events on a population basis.1

Dosing issues

Gla-300 is a subcutaneous injection administered once daily. Each Gla-300 prefilled pen injector contains 450 IU of insulin glargine. The dose to be injected can be adjusted in increments of 1 IU and is shown in the dose counter of the pen. A dose of 1–80 IU can be given in a single injection.5

Unlike Gla-100, Gla-300 is not currently available in a vial.

Recommended initial dosages for Gla-300 are shown below. As with other insulins, subsequent dose adjustment is determined on an individual basis according to patient characteristics and goals of therapy.5,22

Starting insulin

Insulin dosage needs to be individualised for patients starting insulin therapy – consult guidelines.11,22 In type I diabetes mellitus, Gla-300 must be combined with short/rapid-acting insulin in order to cover mealtime insulin requirements. In type 2 diabetes, the recommended daily starting dose is 0.2 IU/kg body weight followed by individual dosage adjustments. Also, for patients with type 2 diabetes mellitus, Gla-300 can be given together with orally active antidiabetic medicinal products.5

Switching between Gla-300 and Gla-100

  • Gla-300 and Gla-100 are not directly interchangeable.
  • When switching from Gla-100 to Gla-300, start with a unit-for-unit dose switch; however, a higher dose of Gla-300 may be required to achieve treatment targets.5
  • When switching from Gla-300 to Gla-100, start with a reduced dose. The starting dose of Gla-100 should be about 20% less than the dose of the Gla-300 being discontinued.5

Switching from other basal insulin

  • From a once-daily insulin: start with a unit-for-unit dose of the basal insulin being discontinued.5
  • From a twice-daily basal insulin: start with 80% of the total daily dose of the basal insulin being discontinued.5

When changing from one basal insulin to another, the dosage of short-acting or very short-acting insulin and oral diabetes medicines may also need to be adjusted.10

Close monitoring of blood glucose is also recommended during the change and in the following weeks.10

Special populations

Gla-300 can be used by older patients (aged ≥ 65 years) but, as with any insulin, should be dosed conservatively to avoid hypoglycaemic events.5

There are no data on the use of Gla-300 during pregnancy or lactation.5 Exercise similar caution when prescribing Gla-300 as with other long-acting insulin formulations for these women.

Avoiding medicine errors

The prefilled pen device for both Gla-300 and Gla-100 is called ‘SoloStar’. To help distinguish between the two glargine products, Gla-300 is branded differently from Gla-100 and the ‘U300’ is highlighted in yellow on the label.5

Patients must exercise all usual precautions associated with use of an insulin pen, such as checking the label, visually verifying the number of selected units on the dose counter of the pen and not reusing needles.5

Administration

Gla-300 is administered once daily by subcutaneous injection in the abdominal, deltoid or thigh region.5

If more than 80 units of insulin are required to deliver a single dose of Gla-300, the split injections should be given at the same time.

Preferably Gla-300 should be administered at the same time each day, but if necessary it can be injected up to 3 hours before or after the usual time of administration.5

Information for patients

Inform the patient and/or carers that Gla-300:5

  • is a long-acting insulin that controls blood glucose levels between meals for 24 hours
  • is administered subcutaneously once daily
  • is not interchangeable with any other basal insulin, including Gla-100, without individualised dose adjustment; blood glucose should be monitored closely during the switch and in the following weeks
  • must not be used together with any other basal insulin
  • is a clear solution and should not be confused with short-acting or very short-acting insulins, which are also clear solutions
  • must not be diluted or mixed with any other insulin
  • should only be administered using the prefilled pen device in which it is provided for use.

Ensure that the patient and/or carers are aware of the warning signs of hypoglycaemia and advise on factors that increase the risk of hypoglycaemia with insulins.

Discuss the Toujeo consumer medicine information (CMI) leaflet with the patient.

References

  1. Australian Government Department of Health. July 2015 PBAC outcomes - positive recommendations. Canberra: DoH, 2015 (accessed 1 October 2015).
  2. Pharmaceutical Benefits Scheme. Public Summary Document - July 2015 PBAC meeting. Insulin glargine, injection, 300 units per ml, Toujeo®, Sanofi Aventis Australia Pty Ltd 2015 (accessed 11 April 2018).
  3. Therapeutic Goods Administration. Public Summary: TOUJEO insulin glargine 300 units/mL solution for injection injector pen. Australian Register of Therapeutic Goods 2015 (accessed August 2015).
  4. Australian Government Department of Health. The Pharmaceutical Benefits Scheme (PBS). Canberra: DoH, 2015 (accessed September 2015).
  5. Sanofi-Aventis Australia Pty Ltd. Toujeo product information. 2015 (accessed August 2015).
  6. Steinstraesser A, Schmidt R, Bergmann K, et al. Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml. Diabetes Obes Metab 2014;16:873–6.
  7. Becker RH, Dahmen R, Bergmann K, et al. New insulin glargine 300 Units mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units mL-1. Diabetes Care 2015;38:637-43.
  8. Pharmaceutical Benefits Scheme. Insulin glargine. 2018 (accessed 12 April 2017).
  9. Pharmaceutical Benefits Scheme. Insulin detemir. 2018 (accessed 12 April 2018).
  10. Endocrinology Expert Group. Therapeutic Guidelines: Diabetes management. West Melbourne, Victoria: Therapeutic Guidelines Ltd, 2013 (accessed 12 April 2018).
  11. Royal Australian College of General Practitioners. General practice management of type 2 diabetes – 2016-18. East Melbourne: RACGP, 2016. (accessed 12 April 2018).
  12. Gunton JE, Cheung NW, Davis TM, et al. A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society. Med J Aust 2014;201:650-3.
  13. Home PD, Bergenstal RM, Bolli GB, et al. New insulin glargine 300 Units/mL versus glargine 100 Units/mL in people with type 1 diabetes: a randomized, phase 3a, open-label clinical trial (EDITION 4). Diabetes Care 2015.
  14. Home PD, Bergenstal RM, Bolli GB, et al. Glycaemic control and hypoglycaemia during 12 months of randomized treatment with insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 1 diabetes (EDITION 4). Diabetes Obes Metab 2018;20:121-8.
  15. Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1). Diabetes Care 2014;37:2755-62.
  16. Yki-Jarvinen H, Bergenstal R, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014;37:3235-43.
  17. Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naive people with type 2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab 2015;17:386-94.
  18. Ritzel R, Roussel R, Giaccari A, et al. Better glycaemic control and less hypoglycaemia with insulin glargine 300 U/mL vs glargine 100 U/mL: 1-year patient-level meta-analysis of the EDITION clinical studies in people with type 2 diabetes. Diabetes Obes Metab 2018;20:541-8.
  19. Ritzel R, Roussel R, Bolli GB, et al. Patient-level meta-analysis of the EDITION 1, 2 and 3 studies: glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes. Diabetes Obes Metab 2015;17:859–67.
  20. Riddle MC, Yki-Jarvinen H, Bolli GB, et al. One-year sustained glycaemic control and less hypoglycaemia with new insulin glargine 300 U/ml compared with 100 U/ml in people with type 2 diabetes using basal plus meal-time insulin: the EDITION 1 12-month randomized trial, including 6-month extension. Diabetes Obes Metab 2015;17:835-42.
  21. Yki-Jarvinen H, Bergenstal RM, Bolli GB, et al. Glycaemic control and hypoglycaemia with new insulin glargine 300 U/mL versus glargine 100 U/mL in people with type 2 diabetes using basal insulin and oral antihyperglycaemic drugs (EDITION 2 randomised 12-month trial including 6-month extension). Diabetes Obes Metab 2015.
  22. Therapeutic Guidelines Limited. eTG complete. West Melbourne: TGA, 2015 (accessed August 2015).