Dulaglutid (2) – Trulicity®

• Clinical trials
  • The REWIND trial is a randomised, double-blind, placebo-controlled, two-arm trial conducted at multiple centres in Africa, Asia, Australia, Europe, and North and South America.
  • The AWARD-6 trial is a two-arm, randomised, actively controlled, open-label trial with a treatment duration of 26 weeks.
  • The AWARD-4 study is a randomised, active-controlled registration trial (Phase III) with a treatment period of 52 weeks.
  • The AWARD-7 study is a three-arm, randomised, actively controlled, open-label Phase III study with a treatment duration of 52 weeks.

a) Adult patients with type 2 diabetes mellitus in whom diet and exercise alone do not adequately control blood glucose levels, and for whom metformin is not suitable due to intolerance

• The additional benefit is not proven.
• No study relevant to the benefit assessment was presented in comparison with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride) that would have been suitable for assessing the additional benefit of dulaglutide monotherapy for the treatment of adult patients with inadequately controlled type 2 diabetes mellitus, in addition to diet and exercise, when metformin is not indicated due to intolerance or contraindications.
• In the REWIND study submitted for the assessment of additional benefit (see above: aspects across patient groups), only 5.4% of patients were treated with dulaglutide without any other antidiabetic medication.
• Furthermore, it is unclear to what extent this applies to these patients, or what proportion of patients met the eligibility criterion of ‘metformin intolerance or contraindication, as an adjunct to diet and exercise’.
• Furthermore, treatment with dulaglutide was administered at twice the dose recommended in the summary of product characteristics (SmPC) for dulaglutide monotherapy.
• Consequently, no meaningful data can be derived from this study for the assessment of the additional benefit of dulaglutide in (antidiabetic) monotherapy in patients with type 2 diabetes mellitus, where diet and exercise alone do not adequately control blood glucose levels and the use of metformin is deemed unsuitable due to intolerance.

b) treatment with another blood-glucose-lowering medicinal product (other than insulin)

• An additional benefit is not proven.
• mortality
  • No deaths occurred.
• morbidity
  • No usable data are available for morbidity endpoints in the patient population.
• Side effects
  • No conclusions regarding statistical significance can be drawn for the overall rates of AEs.
  • No statistically significant differences were observed between the treatment arms in the overall rate of SAEs or in discontinuation due to AEs.
  • No usable data are available for the patient population regarding the other endpoints: non-severe, symptomatic, confirmed hypoglycaemia and severe hypoglycaemia.
• Overall assessment
  • Patient group b) comprises adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with another blood glucose-lowering medicinal product (other than insulin) do not adequately control blood glucose levels.
  • To assess the additional benefit of dulaglutide compared with liraglutide, each in combination with metformin, the pharmaceutical manufacturer presents a patient population from the AWARD-6 study comprising patients with manifest cardiovascular disease.
  • Adult patients with type 2 diabetes mellitus and manifest cardiovascular disease constitute only a subgroup of patient group b). No studies are available for patients with type 2 diabetes mellitus without manifest cardiovascular disease; consequently, no conclusions can be drawn regarding the additional benefit of dulaglutide for patients without manifest cardiovascular disease.
  • Based on the AWARD-6 study in patients with manifest cardiovascular disease, either no statistically significant differences between the treatment arms can be inferred, or no usable data are available for the relevant patient population. Consequently, no conclusions can be drawn on this basis regarding the additional benefit of dulaglutide in this patient group.
  • For the assessment of the REWIND study, reference is made to the above comments on aspects common to all patient groups.
  • Overall, the additional benefit of dulaglutide in combination with other antidiabetic medicines compared with the appropriate comparator therapy for this patient group is not proven.

c) treatment with at least two blood glucose-lowering medicinal products (excluding insulin)

• An additional benefit is not proven.
• Overall assessment
  • Patient group c) comprises adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with at least two blood glucose-lowering medicinal products (excluding insulin) do not adequately control blood glucose levels.
  • Adult patients with type 2 diabetes mellitus and high cardiovascular risk constitute only a subgroup of patient group c). No studies are available for patients with type 2 diabetes mellitus without high cardiovascular risk; consequently, no conclusions can be drawn regarding the additional benefit of dulaglutide for patients without high cardiovascular risk in patient group c).
  • For the assessment of the REWIND study, reference is made to the above comments on aspects common to all patient groups.
  • Overall, the additional benefit of dulaglutide in combination with other antidiabetic agents compared with the appropriate comparator therapy for this patient group is not proven.

d1) treatment with insulin (with or without another blood glucose-lowering agent – in patients without renal insufficiency

• hint of a minor additional benefit.
• Morbidity – Cardiovascular morbidity
  • The endpoint ‘cardiovascular morbidity’ was operationalised by the pharmaceutical manufacturer as the number of patients with at least one adjudicated cardiovascular event, comprising fatal cardiovascular and non-fatal cardiovascular events (SOC for cardiac events). The pharmaceutical manufacturer presents the overall event rates, but not the results for the individual components. Due to the lack of data on the individual components of the composite endpoint, no assessment of this endpoint is carried out.
• Morbidity – Health status (EQ-5D-VAS)
  • Data on health status were collected using the EQ-5D VAS (visual analogue scale of the EuroQol-5D questionnaire). In a direct comparison, no statistically significant difference was observed between dulaglutide and insulin glargine, each in combination with insulin lispro, with or without metformin.
• Side effects – Severe Adverse Events (SAE)
  • For the SAE endpoint (patients with ≥ 1 SAE), a statistically significant treatment difference was observed in favour of dulaglutide + insulin lispro, with or without metformin, compared with insulin glargine + insulin lispro, with or without metformin, for the period up to week 52. Events occurred across all organ systems without any clustering in any particular area.
• Side effects – discontinuation due to adverse events (AE)
  • Treatment with dulaglutide, compared with insulin glargine, in each case in combination with insulin lispro with or without metformin, resulted in a statistically significant higher proportion of patients discontinuing treatment due to AEs for the period up to week 52.
• Side effects – severe hypoglycaemia
  • In the dossier, the pharmaceutical manufacturer includes the criterion of external assistance in the operationalisation of severe hypoglycaemia, in line with the definition of the American Diabetes Association (ADA) used as the operationalisation in the study report. However, external assistance alone is not a sufficiently reliable criterion for severe hypoglycaemia, as this would also occur, for example, following the intake of oral carbohydrates. It cannot therefore be ruled out that ‘non-severe’ cases are also included among the severe hypoglycaemic events. More specific operationalisations would be those that restrict external assistance to medical intervention (such as the administration of glucose or glucagon) or that record episodes of hypoglycaemia that were life-threatening or led to hospitalisation. The operationalisation used here does not ensure that only severe hypoglycaemic episodes are recorded. Consequently, no usable data were available for this endpoint.
• Side effects – gastrointestinal disorders
  • For the endpoint ‘gastrointestinal disorders’ (SOC), a statistically significant difference was observed between the treatment groups, with a disadvantage for dulaglutide compared with insulin glargine, in each case in combination with insulin lispro, with or without metformin.
• Side effects – nausea, diarrhoea, dyspepsia, loss of appetite and vomiting
  • For the endpoints of nausea, vomiting, dyspepsia and loss of appetite, a statistically significant difference was observed in each case to the detriment of dulaglutide compared with insulin glargine.
• Overall assessment
  • Taking an overall view of the results on mortality, morbidity and side effects, there remains one positive and several negative effects for dulaglutide. On balance, the negative effects for the endpoints of discontinuation due to AEs, gastrointestinal disorders, nausea, diarrhoea, vomiting, dyspepsia and loss of appetite do not entirely call into question the advantage of dulaglutide in terms of safety. Nevertheless, they do diminish this advantage, resulting in a minor additional benefit of dulaglutide in combination with insulin lispro (with or without metformin) compared with insulin glargine in combination with insulin lispro.
• Certainty of the evidence (probability of additional benefit)
  • The certainty of the evidence is classified as ‘a hint’.
  • As the results of a single randomised controlled trial (AWARD-4), classification in the ‘Proof’ category is not justified.
  • Overall, the AWARD-4 study exhibits a low risk of bias at the study level, combined with a generally high risk of bias at the endpoint level due to a lack of blinding of the test intervention versus the active comparator. In the overall assessment of additional benefit, the maximum conclusion is that there is a hint of additional benefit.

d2) treatment with insulin (with or without another blood glucose-lowering agent – in patients with moderate or severe renal insufficiency corresponding to chronic kidney disease (CKD) stages 3 and 4, defined by an eGFR value of < 60 to ≥ 15 ml/min/1.73 m²

• Hint for a minor additional benefit.
• Mortality – all-cause mortality
  • Only a few deaths occurred in the study. For the endpoint of all-cause mortality, there was no statistically significant difference between the treatment arms.
• Morbidity – progression to end-stage renal disease
  • The endpoint ‘progression to end-stage renal disease(ESRD) ’ was operationalised on the basis of the following events: stage V chronic kidney disease, the need for renal replacement therapy, or an eGFR < 15 ml/min/1.73 m².
  • No statistically significant differences were observed between the treatment arms for these endpoints.
• Side effects – serious adverse events and discontinuation due to adverse events
  • No conclusions regarding statistical significance can be drawn regarding the overall rate of adverse events (AEs). No statistically significant differences were observed between the treatment arms in the overall rate of serious adverse events (SAEs). For the endpoint ‘discontinuation due to AEs’, there is a statistically significant disadvantage for dulaglutide compared with the control.
• Side effects – Non-severe, symptomatic hypoglycaemia
  • For this endpoint, non-severe, symptomatic, confirmed hypoglycaemic episodes with a plasma glucose (PG) threshold of < 54 mg/dl, and additionally ≤ 70 mg/dl, were taken into account. For both PG < 54 mg/dl and PG ≤ 70 mg/dl, a statistically significant difference was observed in favour of dulaglutide compared with insulin glargine, in each case in combination with insulin lispro.
• Side effects – Severe hypoglycaemia
  • For the endpoint of severe hypoglycaemia, there was a statistically significant advantage for dulaglutide and insulin lispro compared with the comparator arm.
• Side effects – Gastrointestinal disorders
  • For the endpoint of gastrointestinal disorders (SOC) – specifically the PTs ‘nausea’, ‘vomiting’ and ‘diarrhoea’ – statistically significant disadvantages were observed in each case with regard to dulaglutide.
• Overall assessment
  • Overall, the extent of the additional benefit is assessed as minor, taking into account the positive and negative effects of dulaglutide.
• Level of certainty (probability of additional benefit)
  • Overall, the certainty of the evidence is therefore classified as ‘hint’.

Courtesy translation only, please refer to the German original.