TRULICITY Solution for injection Ref.[6812] Active ingredients: Dulaglutide

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, glucagon-like peptide-1 (GLP-1) analogues
ATC code: A10BJ05

Mechanism of action

Dulaglutide is a long-acting glucagon-like peptide 1 (GLP-1) receptor agonist. The molecule consists of 2 identical disulfide-linked chains, each containing a modified human GLP-1 analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy chain fragment (Fc) by a small peptide linker. The GLP-1 analog portion of dulaglutide is approximately 90% homologous to native human GLP-1 (7-37). Native GLP-1 has a half-life of 1.5-2 minutes due to degradation by DPP-4 and renal clearance. In contrast to native GLP-1, dulaglutide is resistant to degradation by DPP-4, and has a large size that slows absorption and reduces renal clearance. These engineering features result in a soluble formulation and a prolonged half-life of 4.7 days, which makes it suitable for once-weekly subcutaneous administration. In addition, the dulaglutide molecule was engineered to prevent the Fcγ receptor-dependent immune response and to reduce its immunogenic potential.

Dulaglutide exhibits several antihyperglycaemic actions of GLP-1. In the presence of elevated glucose concentrations, dulaglutide increases intracellular cyclic AMP (cAMP) in pancreatic beta cells leading to insulin release. Dulaglutide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. Dulaglutide also slows gastric emptying.

Pharmacodynamic effects

Dulaglutide improves glycaemic control through the sustained effects of lowering fasting, pre-meal and postprandial glucose concentrations in patients with type 2 diabetes starting after the first dulaglutide administration and is sustained throughout the once weekly dosing interval.

A pharmacodynamic study with dulaglutide demonstrated, in patients with type 2 diabetes, a restoration of first phase insulin secretion to a level that exceeded levels observed in healthy subjects on placebo, and improved second phase insulin secretion in response to an intravenous bolus of glucose. In the same study, a single 1.5 mg dose of dulaglutide appeared to increase maximal insulin secretion from the β-cells, and to enhance β-cell function in subjects with type 2 diabetes mellitus as compared with placebo.

Consistent with the pharmacokinetic profile, dulaglutide has a pharmacodynamic profile suitable for once weekly administration (see section 5.2).

Clinical efficacy and safety

Glycaemic control

The safety and efficacy of dulaglutide were evaluated in eight randomised, controlled, phase III trials involving 5,770 patients with type 2 diabetes. Of these, 1,139 were ≥65 years of which 115 were ≥75 years. These studies included 3,525 dulaglutide-treated patients, of whom 2,108 were treated with Trulicity 1.5 mg weekly and 1,417 were treated with Trulicity 0.75 mg weekly. In all studies, dulaglutide produced clinically significant improvements in glycaemic control as measured by glycosylated haemoglobin A1c (HbA_1c).

Monotherapy

Dulaglutide was studied in a 52 week active controlled monotherapy study in comparison to metformin. Trulicity 1.5 mg and 0.75 mg were superior to metformin (1500-2000 mg/day) in the reduction in HbA_1c and a significantly greater proportion of patients reached an HbA_1c target of <7.0% and ≤6.5% with Trulicity 1.5 mg and Trulicity 0.75 mg compared to metformin at 26 weeks.

Table 2. Results of a 52 week active controlled monotherapy study with two doses of dulaglutide in comparison to metformin:

^† multiplicity adjusted 1-sided p-value <0.025, for noninferiority; †† multiplicity adjusted 1-sided p-value <0.025, for superiority of dulaglutide to metformin, assessed for HbA_1c only
^# p <0.05, ## p <0.001 dulaglutide treatment group compared to metformin

The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and metformin were 0.62, 0.15, and 0.09 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed.

Combination therapy with metformin

The safety and efficacy of dulaglutide was investigated in a placebo and active controlled (sitagliptin 100 mg daily) study of 104 weeks duration, all in combination with metformin. Treatment with Trulicity 1.5 mg and 0.75 mg resulted in a superior reduction in HbA_1c compared to sitagliptin at 52 weeks, accompanied by a significantly greater proportion of patients achieving HbA_1c targets of <7.0% and ≤6.5%. These effects were sustained to the end of the study (104 weeks).

Table 3. Results of a 104 week placebo and active controlled study with two doses of dulaglutide in comparison to sitagliptin:

^†† multiplicity adjusted 1-sided p-value < 0.025, for superiority of dulaglutide compared to sitagliptin, assessed only for HbA_1c at 52 and 104 weeks
^‡‡ multiplicity adjusted 1-sided p-value < 0.001 for superiority of dulaglutide compared to placebo, assessed for HbA_1c only
** p <0.001 dulaglutide treatment group compared to placebo
^## p <0.001 dulaglutide treatment group compared to sitagliptin

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and sitagliptin were 0.19, 0.18, and 0.17 episodes/patient/year, respectively. No cases of severe hypoglycaemia with dulaglutide were observed.

The safety and efficacy of dulaglutide was also investigated in an active controlled study (liraglutide 1.8 mg daily) of 26 weeks duration, both in combination with metformin. Treatment with Trulicity 1.5 mg resulted in similar lowering of HbA_1c and patients achieving HbA_1c targets of <7.0% and ≤6.5% compared to liraglutide.

Table 4. Results of a 26 week active controlled study of one dose of dulaglutide in comparison to liraglutide:

^‡ 1-sided p-value p <0.001, for noninferiority of dulaglutide compared to liraglutide, assessed only for HbA_1c.
^# p <0.05 dulaglutide treatment group compared to liraglutide.
⁺ Patients randomised to liraglutide were initiated at a dose of 0.6 mg/day. After Week 1, patients were up-titrated to 1.2 mg/day and then at Week 2 to 1.8 mg/day.

The rate of documented symptomatic hypoglycaemia with Trulicity 1.5 mg was 0.12 episodes/patient/year and with liraglutide was 0.29 episodes/patient/year. No cases of severe hypoglycaemia were observed

Combination therapy with metformin and sulphonylurea

In an active controlled study of 78 weeks duration, dulaglutide was compared to insulin glargine, both on a background of metformin and a sulphonylurea. At 52 weeks, Trulicity 1.5 mg demonstrated superior lowering in HbA_1c to insulin glargine which was maintained at 78 weeks; whereas lowering in HbA_1c with Trulicity 0.75 mg was non-inferior to insulin glargine. With Trulicity 1.5 mg a significantly higher percentage of patients reached a target HbA_1c of < 7.0% or ≤ 6.5% at 52 and 78 weeks compared to insulin glargine.

Table 5. Results of a 78 week active controlled study with two doses of dulaglutide in comparison to insulin glargine:

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and insulin glargine were 1.67, 1.67, and 3.02 episodes/patient/year, respectively. Two cases of severe hypoglycaemia were observed with Trulicity 1.5mg and two cases of severe hypoglycaemia were observed with insulin glargine.

Combination therapy with sulphonylurea

The safety and efficacy of dulaglutide as add-on to a sulphonylurea was investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 1.5mg in combination with glimepiride resulted in a statistically significant reduction in HbA_1c compared to placebo with glimepiride at 24 weeks. With Trulicity 1.5 mg, a significantly higher percentage of patients reached a target HbA_1c of <7.0% and ≤6.5% at 24 weeks compared to placebo.

Table 6. Results of a 24 week placebo controlled study of dulaglutide as add-on to glimepiride:

^‡‡ p <0.001 for superiority of dulaglutide compared to placebo, with overall type I error controlled
** p <0.001 for dulaglutide treatment group compared to placebo

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and placebo were 0.90 and 0.04 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for Trulicity or placebo.

Combination therapy with SGLT2 inhibitor with or without metformin

The safety and efficacy of dulaglutide as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin) were investigated in a placebo controlled study of 24 weeks duration. Treatment with Trulicity 0.75 mg or Trulicity 1.5 mg in combination with SGLT2i therapy resulted in a statistically significant reduction in HbA_1c compared to placebo with SGLT2i therapy at 24 weeks. With both Trulicity 0.75 mg and 1.5 mg, a significantly higher percentage of patients reached a target HbA_1c of <7.0% and ≤6.5% at 24 weeks compared to placebo.

Table 7. Results of a 24 week placebo controlled study of dulaglutide as add-on to SGLT2i therapy:

^‡‡ p <0.001 for superiority of dulaglutide compared to placebo, with overall type I error controlled
** p <0.001 for dulaglutide treatment group compared to placebo
^ Patients who withdrew from randomized treatment before 24 weeks were considered as not meeting the target

The rates of documented symptomatic hypoglycaemia with Trulicity 0.75 mg, Trulicity 1.5 mg, and placebo were 0.15, 0.16 and 0.12 episodes/patient/year, respectively. One patient reported severe hypoglycaemia with Trulicity 0.75 mg in combination with SGLT2i therapy and none with Trulicity 1.5 mg or placebo.

Combination therapy with metformin and pioglitazone

In a placebo and active (exenatide twice daily) controlled study, both in combination with metformin and pioglitazone, Trulicity 1.5 mg and 0.75 mg demonstrated superiority for HbA_1c reduction in comparison to placebo and exenatide, accompanied by a significantly a greater percentage of patients achieving HbA_1c targets of <7.0% or ≤6.5%.

Table 8. Results of a 52 week active controlled study with two doses of dulaglutide in comparison to exenatide:

^†† multiplicity adjusted 1-sided p-value <0.025, for superiority of dulaglutide to exenatide, assessed for HbA_1c only
^‡‡ multiplicity adjusted 1-sided p-value <0.001 for superiority of dulaglutide compared to placebo, assessed for HbA_1c only
* p <0.05, **p <0.001 dulaglutide treatment group compared to placebo
^# p <0.05, ##p <0.001 dulaglutide treatment group compared to exenatide
⁺ Exenatide dose was 5 mcg twice daily for first 4 weeks and 10 mcg twice daily thereafter

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and exenatide twice daily were 0.19, 0.14, and 0.75 episodes/patient/year, respectively. No cases of severe hypoglycaemia were observed for dulaglutide and two cases of severe hypoglycaemia were observed with exenatide twice daily.

Combination therapy with titrated basal insulin, with or without metformin

In a 28 week placebo controlled study, Trulicity1.5 mg was compared to placebo as add-on to titrated basal insulin glargine (88% with and 12% without metformin) to evaluate the effect on glycaemic control and safety. To optimise the insulin glargine dose, both groups were titrated to a target fasting serum glucose of <5.6 mmol/L. The mean baseline dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving Trulicity 1.5mg. The initial insulin glargine doses in patients with HbA_1c <8.0% were reduced by 20%. At the end of the 28 week treatment period the dose was 65 units/day and 51 units/day, for patients receiving placebo and Trulicity 1.5 mg, respectively. At 28 weeks, treatment with once weekly Trulicity 1.5 mg resulted in a statistically significant reduction in HbA_1c compared to placebo and a significantly greater percentage of patients achieving HbA_1c targets of <7.0% and ≤6.5% (Table 9).

Table 9. Results of a 28 week study of dulaglutide compared to placebo as add-on to titrated insulin glargine:

^‡‡ p <0.001 for superiority of dulaglutide compared to placebo, overall type I error controlled
** p <0.001 dulaglutide treatment group compared to placebo

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and insulin glargine were 3.38 episodes/patient/year compared to placebo and insulin glargine 4.38 episodes/patient/year. One patient reported severe hypoglycaemia with Trulicity 1.5 mg in combination with insulin glargine and none with placebo.

Combination therapy with prandial insulin with or without metformin

In this study, patients on 1 or 2 insulin injections per day prior to study entry, discontinued their prestudy insulin regimen and were randomised to dulaglutide once weekly or insulin glargine once daily, both in combination with prandial insulin lispro three times daily, with or without metformin. At 26 weeks, both Trulicity 1.5 mg and 0.75mg were superior to insulin glargine in lowering of HbA_1c and this effect was sustained at 52 weeks. A greater percentage of patients achieved HbA_1c targets of <7.0% or ≤6.5% at 26 weeks and <7.0% at 52 weeks than with insulin glargine.

Table 10. Results of a 52 week active controlled study with two doses of dulaglutide in comparison to insulin glargine:

^†† multiplicity adjusted 1-sided p-value <0.025, for superiority of dulaglutide to insulin glargine, assessed for HbA_1c only
^# p <0.05, ##p <0.001 dulaglutide treatment group compared to insulin glargine
⁺ Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of <5.6 mmol/L

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and 0.75 mg, and insulin glargine were 31.06, 35.66, and 40.95 episodes/patient/year, respectively. Ten patients reported severe hypoglycaemia with Trulicity 1.5 mg, seven with Trulicity 0.75 mg, and fifteen with insulin glargine.

Fasting blood glucose

Treatment with dulaglutide resulted in significant reductions from baseline in fasting blood glucose. The majority of the effect on fasting blood glucose concentrations occurred by 2 weeks. The improvement in fasting glucose was sustained through the longest study duration of 104 weeks.

Postprandial glucose

Treatment with dulaglutide resulted in significant reductions in mean post prandial glucose from baseline (changes from baseline to primary time point -1.95 mmol/L to -4.23 mmol/L).

Beta-cell function

Clinical studies with dulaglutide have indicated enhanced beta-cell function as measured by homeostasis model assessment (HOMA2-%B). The durability of effect on beta-cell function was maintained through the longest study duration of 104 weeks.

Body weight

Trulicity 1.5 mg was associated with sustained weight reduction over the duration of studies (from baseline to final time point -0.35 kg to -2.90 kg). Changes in body weight with Trulicity 0.75 mg ranged from 0.86 kg to -2.63 kg. Reduction in body weight was observed in patients treated with dulaglutide irrespective of nausea, though the reduction was numerically larger in the group with nausea.

Patient reported outcomes

Dulaglutide significantly improved total treatment satisfaction compared to exenatide twice daily. In addition, there was significantly lower perceived frequency of hyperglycaemia and hypoglycaemia compared to exenatide twice daily.

Blood pressure

The effect of dulaglutide on blood pressure as assessed by Ambulatory Blood Pressure Monitoring was evaluated in a study of 755 patients with type 2 diabetes. Treatment with dulaglutide provided reductions in systolic blood pressure (SBP) (-2.8 mmHg difference compared to placebo) at 16 weeks. There was no difference in diastolic blood pressure (DBP). Similar results for SBP and DBP were demonstrated at the final 26 week time point of the study.

Cardiovascular Evaluation

In a meta-analysis of phase II and III studies, a total of 51 patients (dulaglutide: 26 [N=3,885]; all comparators: 25 [N=2,125]) experienced at least one cardiovascular (CV) event (death due to CV causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina). The results showed that there was no increase in CV risk with dulaglutide compared with control therapies (HR: 0.57; CI: [0.30, 1.10]).

Special populations

Use in patients with renal impairment

In a 52 week study, Trulicity 1.5 mg and 0.75 mg were compared to titrated insulin glargine as add-on to prandial insulin lispro to evaluate the effect on glycaemic control and safety of patients with moderate to severe chronic kidney disease (eGFR [by CKD-EPI] <60 and ≥15 mL/min/1.73 m²). Patients discontinued their prestudy insulin regimen at randomisation. At baseline, overall mean eGFR was 38 mL/min/1.73 m², 30% of patients had eGFR <30 mL/min/1.73 m².

At 26 weeks, both Trulicity 1.5 mg and 0.75 mg were non-inferior to insulin glargine in lowering of HbA_1c and this effect was sustained at 52 weeks. A similar percentage of patients achieved HbA_1c targets of <8.0% at 26 and 52 weeks with both dulaglutide doses as well as insulin glargine.

Table 11. Results of a 52 week active controlled study with two doses of dulaglutide in comparison to insulin glargine (in patients with moderate to severe chronic kidney disease):

^† 1-sided p-value <0.025, for non-inferiority of dulaglutide to insulin glargine
^## p <0.001 dulaglutide treatment group compared to insulin glargine
⁺ Insulin glargine doses were adjusted utilizing an algorithm with a fasting plasma glucose target of ≤8.3 mmol/L

The rates of documented symptomatic hypoglycaemia with Trulicity 1.5 mg and Trulicity 0.75 mg, and insulin glargine were 4.44, 4.34, and 9.62 episodes/patient/year, respectively. No patients reported cases of severe hypoglycaemia with Trulicity 1.5 mg, six with Trulicity 0.75 mg, and seventeen with insulin glargine. The safety profile of Trulicity in patients with renal impairment was similar to that observed in other studies with Trulicity.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Trulicity in one or more subsets of the paediatric population for the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).