Initiating treatment with dulaglutide or liraglutide for type 2 diabetes

Although dulaglutide (Trulicity) stock volumes in New Zealand are currently sufficient, increased demand for GLP-1 receptor agonists (GLP1RAs) globally has placed uncertainty around ongoing uninterrupted supplies. While dulaglutide remains available now, the uncertainties around its supply are likely to remain for some time.

In response to this potential supply issue, Pharmac has funded liraglutide (Victoza brand only) as an alternative to dulaglutide to ensure that funded GLP1RAs remain available for existing and new people who need them.

Prescribers and patients can decide, based on clinical circumstances, which of the two funded GLP1RAs would be most suitable. The Special Authority criteria are the same for both agents, and there are no funding restrictions stopping existing dulaglutide patients from moving to liraglutide (Victoza).

Update: From 1 November 2023, the Special Authority criteria for GLP1RAs will be amended so that new initiations are restricted to people with type 2 diabetes who are high-risk and have no other appropriate treatment options. This change is to ensure people currently taking dulaglutide or liraglutide can continue to access these medicines.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone released from gut enteroendocrine cells in response to food intake. It controls meal-related glycaemic excursions through the augmentation of glucose-dependent insulin secretion and inhibition of glucagon secretion. GLP-1 also has important actions on slowing gastric emptying and reducing appetite and food intake.¹

Endogenous GLP-1 is a physiological regulator known to have the following actions:

• enhances insulin secretion by pancreatic beta cells in the presence of raised glucose concentrations
• suppresses secretion of glucagon (often inappropriately elevated in type 2 diabetes) by pancreatic alpha cells
• slows gastric emptying
• signals satiety to the brain.^1–3

GLP-1 receptors are expressed in the pancreatic islet cells, several areas of the brain involved in appetite regulation, and in specific locations in the heart, vasculature, immune system and kidneys.³

In type 2 diabetes, by interacting with these receptors, the human GLP-1 receptor agonist (GLP1RA) class of medicines (eg, dulaglutide, liraglutide) affect blood glucose control in several ways – they reduce fasting blood glucose levels, postprandial blood glucose levels and appetite.⁴

GLP1RAs and sodium–glucose cotransporter-2 (SGLT2) inhibitors (eg, empagliflozin) are effective agents for people with type 2 diabetes and cardiovascular disease (CVD) and/or renal disease. They both reduce mortality from cardiovascular events and renal disease progression independent of their effects on glycaemic control. GLPRA1s lead to the most weight loss of all the available glucose-lowering agents, reduce blood pressure, and do not cause hypoglycaemia in the absence of other glucose-lowering agents.⁵

In New Zealand, dulaglutide (Trulicity)^6,7 and liraglutide (Victoza brand only)^3,7 are registered for use in patients with type 2 diabetes mellitus for:

• glycaemic control
• prevention of major adverse cardiovascular events (MACE).

It is important to note that, in New Zealand, liraglutide (Saxenda) is a separately marketed product registered for use in weight management only and remains unfunded – see section at the end of this article on patients already using Saxenda.

Dulaglutide and liraglutide (Victoza) are suitable for use in type 2 diabetes as monotherapy or in combination with other blood glucose-lowering treatments (including insulin). See the He Ako Hiringa algorithm: “Initiating treatment with dulaglutide or liraglutide in adult patients with type 2 diabetes”.⁹

Important points to note include:

• Metformin remains the first-line treatment for type 2 diabetes and should be continued unless contraindicated or not tolerated.²
• A GLP1RA should not be used in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor (eg, vildagliptin, sitagliptin, saxagliptin) because the introduction of the GLP1RA makes use of the DPP-4 inhibitor redundant, and adverse effects may be increased with concomitant treatment.⁵
• A GLP1RA can be used in conjunction with an SGLT2 inhibitor – empagliflozin in New Zealand – however, either the GLP1RA or SGLT2 inhibitor must be privately funded (the cheaper option is to self-fund the SGLT2 inhibitor). Empagliflozin in type 2 diabetes offers the greatest benefit (and is the preferred choice over a GLP1RA) in the setting of heart failure (particularly with reduced ejection fraction) or predominant diabetic kidney disease (DKD).⁵ In these patients, a GLP1RA is a useful alternative when the SGLT2 inhibitor is not tolerated or is contraindicated, or is the next best agent to add for glycaemic control.⁵ [See the He Ako Hiringa algorithm resource: “Initiating treatment with empagliflozin in adult patients with type 2 diabetes”].⁸
• Contraindications to the use of a GLP1RA include hypersensitivity to liraglutide or any of its excipients, type 1 diabetes (GLP1RAs are not a substitute for insulin), treatment of diabetic ketoacidosis, personal or family history of medullary thyroid carcinoma and patients with multiple endocrine neoplasia syndrome type 2.²
• Special precautions and warnings include (see respective datasheets^3,6 for full details):
  • severe gastrointestinal disease (including gastroparesis)
  • acute pancreatitis (observed with GLP1RA use – advise patients of characteristic symptoms and to stop medication and seek medical help if these present)
  • dehydration (including renal impairment and acute renal failure) – reported in patients using a GLP1RA (advise patient of potential risk in relation to gastrointestinal side effects and to take precautions to avoid fluid depletion)
  • end-stage renal disease (<15 ml/min requiring dialysis)
  • hypoglycaemia – see below.
• When introducing a GLP1RA to a patient already using insulin or a sulfonylurea, there can be an increased risk of hypoglycaemic episodes. The patient’s HbA1c must be considered and dose adjustments to insulin or the sulfonylurea may need to be made. Patients with an HbA1c ≥ 75mmol/mol with no episodes of hypoglycaemia will typically not require any reduction in insulin and/or sulfonylureas when starting a GLP1RA.⁵Any dose reduction for these medicines is best based on blood glucose levels. Recommended proactive reductions in those with tight glycaemic control (eg, HbA1c <64mmol/mol) include:
  • a 15–20% reduction in total daily insulin; consider switching premixed insulin or ‘basal plus one’ insulin regimens to basal insulin alone
  • a 50% reduction in sulfonylurea doses; consider stopping sulfonylureas for those on ≤80 mg of gliclazide per day or ≤5 mg of glipizide per day.

The Special Authority access criteria for funded dulaglutide and liraglutide (Victoza) for use in type 2 diabetes are the same; however, from 1 March 2023, each has its own Special Authority application number (click on the SA number in the Pharmaceutical Schedule to see the funding eligibility criteria):

• dulaglutide (Trulicity): SA2065
• liraglutide (Victoza): SA2187.

The He Ako Hiringa algorithm for initiating treatment with dulaglutide or liraglutide in adult patients with type 2 diabetes⁹ gives a step-by-step approach to identifying patients eligible for a funded GLP1RA, and outlines contraindications, precautions and when to adjust insulin and/or sulfonylurea doses.

Both agents are GLP-1 receptor agonists, but do they differ?

Highly similar efficacy and adverse event rates

Dulaglutide 1.5mg/week and liraglutide (Victoza) 1.8mg/day are comparable in important respects. At these doses, once-weekly dulaglutide is non-inferior (of equivalent potency) to once-daily liraglutide for least-squares mean reduction in HbA1c, with a similar safety and tolerability profile (AWARD-6).¹⁰

The AWARD-6 non-inferiority trial was performed in patients with type 2 diabetes using metformin with a baseline HbA1c level ≥53mmol/mol and ≤86mmol/mol. The mean reduction in HbA1c over 26 weeks with the additional use of dulaglutide and liraglutide was -1.42% and -1.36%, respectively [a non-inferiority margin for the study was 0.4%; mean treatment difference was -0.06% (95% confidence interval -0.19 to 0.07, p non-inferiority <0.0001)].¹⁰

The most common adverse events reported were gastrointestinal, with similar rates of study, or study drug, discontinuation because of adverse events between the two groups (6 per cent in each). No severe hypoglycaemia was reported in either group.¹⁰

Two further trials have focused on efficacy in terms of reduction in the primary combined endpoint of death from cardiovascular cause, non-fatal myocardial infarction, or non-fatal stroke in patients with type 2 diabetes with high CVD risk. The risk reduction [hazard ratio] in the primary endpoint attributable to standard care plus the study drug, versus standard care plus placebo, was 0.88 for dulaglutide 1.5mg/week (REWIND trial, median follow-up 5.4 years)¹¹ and 0.87 for liraglutide 1.8mg/day (LEADER trial, follow-up 3.8 years).¹²

Differences in dosage, frequency and delivery

Where dulaglutide and liraglutide (Victoza) noticeably differ is in their dosage, frequency and the delivery device used. This is an area where prescribers and patients will need education and to be alert.

Dulaglutide 1.5mg is delivered once weekly using a single-use, subcutaneous autoinjector pen. The dose can be administered at any time of the day, with or without meals, and can be injected subcutaneously in the abdomen, thigh, or upper arm.⁶

Liraglutide (Victoza) is delivered once-daily, subcutaneously in the same sites as dulaglutide using a titratable-dose, multi-use, subcutaneous autoinjector pen. The Victoza pen contains 18mg liraglutide in 3ml solution, providing:

• 30 doses of 0.6mg or
• 15 doses of 1.2mg or
• 10 doses of 1.8mg.

Patients starting liraglutide are advised to begin with 0.6mg/day for one week to improve gastrointestinal tolerability, increasing to 1.2mg/day in week two if tolerated and, if the glycaemic response has not met target HbA1c, the prescriber may recommend an increase to 1.8mg/day. (The increase to 1.8mg can be within two or three weeks if measurements show blood glucose levels are still high and the drug is being tolerated.)⁵ Doses above 1.8mg/day are not recommended. The dose can be given at any time of day, with or without meals, but settling on a preferred regular time of day is advised.³

Switching from dulaglutide to liraglutide

If a patient should need to be switched from dulaglutide 1.5mg/week to liraglutide (Victoza), the same gradual dose escalation, starting at liraglutide 0.6mg/day, should be followed.⁵

Full product details and supportive evidence can be found in the respective data sheets for dulaglutide⁶ and liraglutide (Victoza).³

Health Navigator has produced patient resources for dulaglutide¹³ and liraglutide (Victoza)¹⁴ which give useful information for users of the medicines.

Patient suitability and the access criteria for starting a patient with type 2 diabetes on funded liraglutide (Victoza) are described in the product data sheet,³NZ Formulary,¹⁵ Pharmac access criteria (Special Authority SA2187)¹⁶ and the He Ako Hiringa resource: “Initiating treatment with dulaglutide or liraglutide: Algorithms, notes and talking points.”⁹

Liraglutide (Victoza) was listed on the Pharmaceutical Schedule on 1 March 2023 and supply became available in early March 2023.¹⁷ Initial applications for funded liraglutide (Victoza) can be made now and for the duration of any supply issue impacting dulaglutide. Once the dulaglutide supply issue has resolved, people who have started treatment on funded liraglutide (Victoza) will continue to be able to receive it.¹⁷

In the event of a supply issue causing a dulaglutide product shortage in New Zealand, it will be important to protect and promote treatment adherence. The additional option of being able to start new patients on liraglutide (Victoza) will help ensure existing patients on dulaglutide can continue using a GLP1RA. It will also allow new initiations of dulaglutide to continue in this scenario.

For a number of patients who start a GLP1RA after March 2023 there may be reasons why dulaglutide is chosen rather than liraglutide (Victoza) [eg, tolerability, preference for weekly administration, a carer is required to administer the dose (weekly would be easier to manage)]. Conversely, the titratable dose offered with liraglutide (Victoza) may better suit some patients.

As with dulaglutide, liraglutide (Victoza) is not funded in combination with an SGLT2 inhibitor (empagliflozin), but private funding may be discussed for concomitant therapy.⁵

Injection needles are not included with liraglutide (Victoza). Practitioners will need to prescribe BD needles (4mm or 5mm), which are funded, and ensure sharps disposal is implemented as per local guidelines.⁵ Liraglutide (Victoza) can be administered with needles up to a length of 8mm and as fine as 32G. The pen is designed to be used with NovoFine® disposable needles.³

The Victoza pen should be stored between uses without an injection needle attached. This prevents contamination, infection and leakage. It also ensures that the dosing is accurate.³

Patients starting a GLP1RA should be advised of the potential adverse effects and reassured that mild symptoms typically resolve despite continuing treatment. The most common reported events are:³

• gastrointestinal – nausea, vomiting, anorexia and diarrhoea
• injection site reactions (eg, nodules) – typically transient and improve on continued treatment.

A number of people in New Zealand are already using privately funded liraglutide (Saxenda) for weight management at doses typically in the range 1.8–3.0mg daily, given subcutaneously.¹⁸ The new funding arrangement for liraglutide (Victoza) does not allow for its use in weight management; however, should patients using Saxenda also have type 2 diabetes and meet the access criteria for Victoza, a change to the funded product would be possible (for a dose of 1.8mg daily maximum). A patient search for users of Saxenda may be worthwhile.

Information from New Zealand data sheets unless otherwise indicated