Key points from the evidence

Summary

For reducing HbA1c levels in people with type 2 diabetes, dulaglutide once weekly, when added to metformin, was statistically superior to exenatide twice daily (both in combination with pioglitazone), statistically superior to sitagliptin and statistically non‑inferior to liraglutide 1.8 mg daily. As with the other glucagon‑like peptide‑1 (GLP‑1) receptor agonists there are limited data from randomised controlled trials (RCTs) on the effect of dulaglutide on patient‑oriented outcomes, such as rates of macrovascular or microvascular events, or on long‑term safety.

Regulatory status: Dulaglutide (Trulicity) received a European marketing authorisation in November 2014 and was launched in the UK in January 2015.

Effectiveness

  • Dulaglutide 1.5 mg or 0.75 mg once weekly was superior to placebo (treatment difference −11.5 mmol/mol [­1.05% points] and −9.2 mmol/mol [­0.84% points], respectively) and to exenatide twice daily (treatment difference −5.7 mmol/mol [­0.52% points] and −3.4 mmol/mol [­0.31% points], respectively) for change in HbA1c from baseline (1 RCT, n=978, 26 weeks).

  • Dulaglutide 1.5 mg or 0.75 mg once weekly was superior to sitagliptin once daily (treatment difference −7.8 mmol/mol [­0.71% points] and −5.1 mmol/mol [­0.47% points] respectively) for change in HbA1c from baseline (1 RCT, n=1098, 52 weeks).

  • Dulaglutide 1.5 mg once weekly was non‑inferior to liraglutide 1.8 mg once daily (treatment difference ­0.66 mmol/mol [­0.06% points]) for change in HbA1c from baseline (1 RCT, n=599, 26 weeks).

Safety

  • According to the summary of product characteristics, the most common adverse events (1 in 10 people or more) are hypoglycaemia, particularly in combination with a sulfonylurea or insulin, and gastrointestinal disorders.

  • According to the European public assessment report (EPAR) possible long‑term safety concerns of pancreatitis and pancreatic and thyroid cancers are consistent with other GLP‑1 receptor agonists.

Patient factors

  • Dulaglutide is given once weekly by subcutaneous injection.

  • The EPAR states that the overall effect of dulaglutide on weight was modest across the AWARD trials (mean changes ­0.87 kg to ­3.03 kg), and that the clinical relevance of the observed effect size with the 1.5 mg dose is uncertain.

  • According to the summary of product characteristics injection site reactions are uncommon with dulaglutide (more than 1 in a 1000 people to less than 1 in 100).

  • There are no comparative data with other weekly dose GLP‑1 receptor agonists.

Resource implications

  • The annual cost of dulaglutide 1.5 mg or 0.75 mg once weekly is £1182.35.

  • Annual costs for other GLP‑1 receptor agonists range from £705.75 to £954.84 (excluding VAT; prices taken from Drug Tariff May 2015 or MIMS, May 2015).

Introduction and current guidance

The NICE guideline on type 2 diabetes states that managing type 2 diabetes is complex. It involves individualising a multifactorial approach, addressing blood pressure, blood lipids and lifestyle issues, as well as blood glucose. This guideline is being updated (date of publication to be confirmed). The GLP‑1 receptor agonists exenatide, liraglutide and lixisenatide will be included in the update, but dulaglutide will not be included as the licence was not granted in time for inclusion in the scope of the guideline.

Full text of introduction and current guidance.

Product overview

Dulaglutide (Trulicity, Eli Lilly and Company) is a GLP‑1 receptor agonist. It was launched in the UK in January 2015 for the treatment of type 2 diabetes mellitus in adults to improve glycaemic control as:

  • Monotherapy: when diet and exercise alone do not provide adequate glycaemic control in people for whom the use of metformin is considered inappropriate due to intolerance or contraindications.

  • Add‑on therapy: in combination with other glucose‑lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.

The recommended dose is 0.75 mg once weekly as monotherapy and 1.5 mg once weekly as add‑on therapy, by subcutaneous injection. A reduction in the dose of sulfonylurea or prandial insulin may be considered to reduce the risk of hypoglycaemia when dulaglutide is used in combination with these therapies.

For potentially vulnerable populations, such as people aged 75 years or older, 0.75 mg once weekly can be considered as a starting dose. For people with mild or moderate renal impairment no dose adjustment is necessary. Dulaglutide is not recommended for people with severe renal impairment (eGFR less than 30 ml/minute/1.73 m2) or on dialysis.

Full text of product overview.

Evidence review

  • Dulaglutide has been studied in 6 phase III randomised controlled trials (RCTs) in a broad population of people with type 2 diabetes. This evidence summary is based on 3 of the RCTs that have been published in full. These are AWARD 1 (Wysham et al. 2014), AWARD 5 (Nauck et al. 2014) and AWARD 6 (Dungan et al. 2014). Dulaglutide has been compared with insulin glargine in combination with metformin and glimepiride (AWARD 2, Giorgino et al. 2015), and in combination with prandial insulin lispro with or without metformin (AWARD 4, Blonde et al. 2015). Data from AWARD 2 and 4 studies included in the European public assessment report for dulaglutide (Trulicity) (EPAR) have been used to supplement data from the 3 published studies included in this evidence summary.

  • In AWARD 1 (Wysham et al. 2014) dulaglutide 1.5 mg and 0.75 mg once weekly (added to metformin and pioglitazone) were superior to placebo and exenatide twice daily for change in HbA1c from baseline (average 65.0 mmol/mol [8.1%], p<0.001 for all comparisons). At 26 weeks, the reduction in HbA1c was 16.5 mmol/mol (1.51%) with dulaglutide 1.5 mg; 14.2 mmol/mol (1.30%) with dulaglutide 0.75 mg; 10.8 mmol/mol (0.99%) with exenatide; and 5.0 mmol/mol (0.46%) with placebo.

  • In AWARD 5 (Nauck et al. 2014) dulaglutide 1.5 mg and 0.75 mg once weekly were superior to sitagliptin 100 mg once daily (all in addition to background metformin 1500 mg or more daily) for change in HbA1c from baseline (average 65.0 mmol/mol [8.1%], p<0.001 for both comparisons). At 52 weeks, the reduction in HbA1c was 12.0 mmol/mol (1.10%) with dulaglutide 1.5 mg; 9.5 mmol/mol (0.87%) with dulaglutide 0.75 mg; and 4.3 mmol/mol (0.39%) with sitagliptin.

  • In AWARD 6 (Dungan et al. 2014) dulaglutide 1.5 mg once weekly was non‑inferior to liraglutide 1.8 mg once daily (both in addition to pre‑existing stable metformin 1500 mg or more daily) for change in HbA1c from baseline (average 65.0 mmol/mol [8.1%]). At 26 weeks, the reduction in HbA1c was 16 mmol/mol (1.42%) with dulaglutide compared with 15 mmol/mol (1.36%) with liraglutide (p<0.0001 for non‑inferiority).

  • A weight reduction from baseline of between 0.87 kg and 3.03 kg was seen with dulaglutide 1.5 mg in the 6 RCTs in the AWARD programme. Weight loss with dulaglutide 1.5 mg once weekly was similar to that seen with exenatide 10 microgram twice daily and less than that seen with liraglutide 1.8 mg daily.

  • The EPAR states that across the phase II and III integrated safety population (n=4006), the incidence of common events such as gastrointestinal (GI) disorders are consistent with those previously reported for other GLP‑1 receptor agonists. The incidence of adverse events was generally dose‑related. In AWARD 1 (Wysham et al. 2014) the incidence of GI events was 47% in the dulaglutide 1.5 mg once weekly group and 42% in the exenatide 10 microgram twice daily group. In AWARD 6 (Dungan et al. 2014) the incidence was 36% in both the dulaglutide 1.5 mg once weekly and liraglutide 1.8 mg once daily groups.

  • At the primary end point, the mean event rate of symptomatic hypoglycaemia was 0.34 events per person per year for dulaglutide 1.5 mg once weekly compared with 0.52 for liraglutide 1.8 mg daily (AWARD 6, Dungan et al. 2014) and the mean event rates were 0.45, 1.10, 1.47 and 0.37 events per person per year for dulaglutide 1.5 mg, dulaglutide 0.75 mg, exenatide 10 microgram twice daily and placebo respectively in AWARD 1 (Wysham et al. 2014). According to the Trulicity summary of product characteristics incidences of documented symptomatic hypoglycaemia increased when dulaglutide was used in combination with a sulphonylurea (plus metformin) or with prandial insulin.

  • The Trulicity summary of product characteristics states that injection site reactions are uncommon (incidence more than 1 in 1000 to less than 1 in 100). In AWARD 6 (Dungan et al. 2014) injection site reaction occurred in 0.3% of the dulaglutide group compared with 0.7% of the liraglutide group (at the highest dose) and 1 injection site reaction was reported in each of the dulaglutide 1.5 mg and exenatide groups in AWARD 1 (Wysham et al. 2014).

  • The Trulicity summary of product characteristics states that small mean increases in PR interval (2 to 3 milliseconds from baseline compared with placebo) and a 2.4% incidence of first‑degree atrioventricular block are observed with dulaglutide 1.5 mg in people with normal conduction at baseline. According to the EPAR, an event‑driven cardiovascular outcome study is underway and is estimated to report in 2019.

  • There are limited data on the use of dulaglutide in certain populations, such as people older than 75 years and people with renal or hepatic disease and heart failure. Long‑term safety data are also limited; only 9% of the integrated phase II and III safety population quoted in the EPAR received dulaglutide for up to 2 years and less than half received the 1.5 mg dose.

  • As with the other GLP‑1 receptor agonists, there are limited data from RCTs of dulaglutide relating to patient‑oriented outcomes, such as rates of macrovascular or microvascular events. The evidence of efficacy relates solely to surrogate end points, chiefly reductions in HbA1c compared with a range of other agents, but not compared directly to other once weekly dosing GLP‑1 receptor agonists. The clinical significance of the data needs to be considered in the context of the wider evidence base for the management of type 2 diabetes.

Full text of evidence review.

Context

Other currently licensed GLP‑1 receptor agonists are exenatide, liraglutide and lixisenatide.

Dulaglutide is available as a 4‑pre‑filled pen pack (4 weeks supply) of 0.75 mg/0.5 ml pre‑filled pens or 1.5 mg/0.5 ml pre‑filled pens. Both strengths cost £90.95 per pack (excluding VAT; prices taken from MIMS, May 2015).

The annual cost of dulaglutide 0.75 mg or 1.5 mg once weekly is £1182.35. Annual costs for other GLP‑1 receptor agonists range from £705.75 to £941.76. The other once weekly GLP‑1 analogue is £818.88 per person per year (excluding VAT; prices taken from Drug Tariff May 2015 or MIMS, May 2015).

Full text of context.

Estimated impact for the NHS

The current NICE guidance on the management of type 2 diabetes recommends the use of the GLP‑1 receptor agonists, exenatide or liraglutide in dual or triple therapy in certain circumstances. For continuing treatment beyond 6 months, the guideline recommends a reduction in HbA1c of at least 1.0% point (11 mmol/mol) and a weight loss of at least 3% of initial body weight. The results from AWARD 1, 5 and 6 suggest that dulaglutide 1.5 mg would achieve a reduction in HbA1c of at least 1.0% point (11 mmol/mol).

The HbA1c lowering effect of dulaglutide has been compared with various other blood glucose controlling treatments. Dulaglutide once weekly in combination with metformin and pioglitazone has been shown to be superior to exenatide twice daily and, in combination with metformin, superior to sitagliptin once daily and non‑inferior to liraglutide 1.8 mg once daily, in reduction of HbA1c. However, the clinical significance of these treatment differences remains uncertain with respect to microvascular and macrovascular outcomes.

In the 3 RCTs reviewed in this evidence summary, weight loss with dulaglutide 1.5 mg once weekly was similar to that seen with exenatide 10 microgram twice daily and less than that seen with liraglutide 1.8 mg once daily.

The European public assessment report for dulaglutide (Trulicity) states that the incidence of common adverse events with dulaglutide is consistent with that previously reported for other GLP‑1 receptor agonists and the possible long‑term safety concerns of pancreatitis and pancreatic and thyroid cancers are also the same.

Dulaglutide is given once weekly, which some people may prefer to the once or twice daily dosing of some other GLP‑1 receptor agonists.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.