Dulaglutid (1) – Trulicity®

• Clinical trials
  • This was a randomised, active-controlled, double-blind registration trial (Phase II/III) comparing dulaglutide and sitagliptin, each in combination with metformin, which was divided into two stages (AWARD-5).
  • The AWARD-4 study was a randomised, active-controlled registration trial (Phase III) with a treatment period of 52 weeks.
  • The AWARD-2 study was a 1:1:1 randomised, open-label study with a 52-week treatment duration, in which 810 patients were enrolled.

a) As monotherapy, when diet and exercise alone are insufficient to control blood glucose levels in patients for whom the use of metformin is considered unsuitable due to contraindications or intolerance

• For monotherapy with dulaglutide, where diet and exercise alone are insufficient to control blood glucose levels and the use of metformin is considered unsuitable due to contraindications or intolerance, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of dulaglutide monotherapy, in the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride).

b1) In dual combination therapy with an oral antidiabetic agent, if this, together with diet and exercise, does not adequately control blood glucose – In dual combination with metformin

• For dulaglutide in dual combination therapy with metformin, if metformin, together with diet and exercise, does not sufficiently lower blood glucose levels, the additional benefit compared with the appropriate comparator therapy—metformin in combination with glimepiride—is not proven on the basis of the indirect comparison presented, in accordance with the criteria set out in Section 5(7) of the AM-NutzenV.
• mortality
  • In the AWARD-5 study, there was one death in the dulaglutide + metformin group. In the HARMONY 3 study, there were three deaths in the glimepiride + metformin group. No statistically significant difference in overall mortality was observed between the treatment groups.
  • An additional benefit of dulaglutide + metformin compared with glimepiride + metformin is not proven for overall survival.
• morbidity
  • No data were available for dulaglutide (in combination with metformin) that could be used for a direct or indirect comparison regarding microvascular and macrovascular complications or cardiovascular morbidity.
  • These are urgently required due to the chronic nature of type 2 diabetes mellitus and the resulting long-term treatment of patients.
• Morbidity – Change in HbA1c
  • A comparison of HbA1c levels between dulaglutide + metformin (AWARD-5) and glimepiride + metformin (HARMONY 3) shows, with comparable baseline HbA1c levels, a greater reduction in HbA1c levels with dulaglutide treatment than with glimepiride treatment. The change at week 104 is statistically significant (mean difference = -0.59 [-0.84; -0.34]; p = <0.001).
• Morbidity – Weight loss
  • Furthermore, weight loss (mean difference = -3.17, 95% CI [-4.09; -2.25], p < 0.001) was observed. However, the significance or impact of the observed weight loss over the long term, particularly with regard to cardiovascular safety, remains unclear.
• Health-related quality of life
  • No usable data on quality of life are available, neither for a direct nor for an indirect comparison.
• Side effects – severe adverse events (SAEs) and discontinuation due to adverse events (AEs)
  • For the endpoints SAE and discontinuation due to AEs, no statistically significant differences were observed between the treatment groups in the indirect comparison.
  • For the endpoint ‘study discontinuations due to AEs’, it should be noted that in the AWARD-5 study, ‘persistent hyperglycaemia’ was defined using strict cut-off values for fasting blood glucose and HbA1c, and that patients who met these criteria were required to withdraw from the study due to inadequate glycaemic control, and these withdrawals are included in the total number of study withdrawals.
• Side effects – Symptomatic hypoglycaemia
  • For symptomatic hypoglycaemia with a blood glucose threshold of ≤ 70 mg/dl, there is a statistically significant difference in favour of dulaglutide + metformin compared with glimepiride + metformin (RR = 0.18; 95% CI [0.06; 0.51]; p = 0.001).
  • This indicates that dulaglutide + metformin results in minor harm for the endpoint of symptomatic hypoglycaemia compared with the appropriate comparator therapy (glimepiride in combination with metformin).
• Side effects – severe hypoglycaemia
  • In the dossier, the pharmaceutical manufacturer includes the criterion of requiring 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.
  • As no events occurred in the two relevant study arms during the period under review, this has no bearing on the assessment; it is not proven that dulaglutide + metformin causes greater or minor harm compared with glimepiride + metformin.
• Side effects – gastrointestinal disorders
  • For the endpoint ‘gastrointestinal disorders’ (SOC according to MedDRA), no statistically significant difference between the treatment groups was observed in the indirect comparison.
  • It is therefore not possible to conclude that dulaglutide + metformin causes either greater or minor harm compared with the appropriate comparator therapy, metformin + sulphonylurea (glibenclamide or glimepiride).
• Side effects – nausea, diarrhoea and vomiting
  • For the endpoints of nausea (relative risk (RR) = 3.32; 95% CI [1.50; 7.38]; p = 0.003), diarrhoea (RR = 3.11; 95% CI [1.48; 6.52]; p = 0.003) and vomiting (RR = 4.64; 95% CI [1.68; 12.85]; p = 0.003), a statistically significant difference in treatment outcomes was observed in each case, to the detriment of dulaglutide + metformin compared with glimepiride + metformin.
  • According to the study report for the AWARD-5 trial, patients predominantly rated these gastrointestinal side effects as mild to moderate.
  • For the endpoints of nausea, diarrhoea and vomiting, an overall analysis of the data presented indicates greater adverse effects with dulaglutide + metformin compared with the appropriate comparator therapy of metformin + sulphonylurea (glibenclamide or glimepiride).
• Side effects – injection site reactions
  • For the endpoint ‘injection site reactions’ (SOC), an indirect comparison shows no statistically significant difference between the treatment groups.
  • Consequently, there is no greater or minor harm associated with dulaglutide + metformin compared with the appropriate comparator therapy, metformin + glimepiride.
• Side effects – pancreatitis
  • No patient in either of the two relevant treatment arms, dulaglutide + metformin and glimepiride + metformin, developed pancreatitis confirmed by an independent committee.
  • Consequently, there is no greater or minor risk associated with dulaglutide + metformin compared with the appropriate comparator therapy, metformin + glimepiride.
• Overall assessment
  • In the overall assessment of the results in the ‘side effects’ category, the advantage of dulaglutide in preventing symptomatic, non-serious hypoglycaemia (blood glucose <70 mg/dl) disadvantages in terms of several other non-serious adverse gastrointestinal events, namely the occurrence of nausea, diarrhoea and vomiting.
  • After weighing up the clinical relevance of the benefits and disadvantages regarding these adverse effects, an additional benefit for dulaglutide in dual combination with metformin compared with the appropriate comparator therapy of metformin in combination with glimepiride is not proven.

b2) In dual combination therapy with an oral hypoglycaemic medicinal product (other than metformin), where this, together with diet and exercise, does not adequately control blood glucose

• For combination therapy with dulaglutide and another oral hypoglycaemic medicinal product other than metformin, where diet and exercise alone do not adequately control blood glucose and the use of metformin is considered unsuitable due to intolerance, the additional benefit is not proven.
• No study has been submitted that would have been suitable for assessing the additional benefit of treatment with dulaglutide in combination with another blood glucose-lowering medicinal product other than metformin and insulin, within the above-mentioned therapeutic indication, compared with the appropriate comparator therapy (metformin + sulphonylurea).

c) In triple combination therapy with two oral antidiabetic agents, where these, together with diet and exercise, do not adequately control blood glucose

• For the combination of dulaglutide with two oral blood glucose-lowering medicinal products, where these, in addition to diet and exercise, do not adequately control blood glucose, the additional benefit is not proven.
• There are therefore no suitable data available for the triple combination therapy of dulaglutide with two oral antidiabetic agents to assess the additional benefit compared with the appropriate comparator therapy (metformin + human insulin); an additional benefit is therefore not proven.

d) In combination with insulin, with or without an oral antidiabetic agent, where these, together with diet and exercise, do not adequately control blood glucose

• The G-BA assesses the extent of the additional benefit of dulaglutide (in combination with a short-acting insulin, with or without metformin) compared with the appropriate comparator therapy of metformin + human insulin as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic goal in the treatment of the condition.
• The certainty of the evidence (probability of additional benefit) is classified as ‘hint’.
• mortality
  • In the AWARD-4 study, there was a total of one death in the dulaglutide + insulin lispro group (with or without metformin) and three deaths in the insulin glargine group in combination with insulin lispro (with or without metformin).
  • No statistically significant difference in overall mortality was observed between the treatment groups.
  • An additional benefit of dulaglutide + metformin compared with glimepiride + metformin for overall survival is not proven.
• 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 and non-fatal cardiovascular events (SOC for cardiac events).
  • As the individual components of the composite endpoint are not specified, no assessment of this endpoint is provided.
  • Consequently, no usable (long-term) data are available for dulaglutide (in combination with insulin, with or without metformin) regarding microvascular and macrovascular complications.
• 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.
  • For the health status endpoint (EQ-5D-VAS), therefore, the additional benefit of dulaglutide compared with the appropriate comparator therapy of human insulin plus metformin is not proven.
• Morbidity – Change in HbA1c
  • The primary endpoint selected in the study – change in HbA1c from baseline to week 26 – represents a surrogate parameter in the treatment of diabetes mellitus.
  • At 52 weeks, a significant treatment difference was observed in favour of dulaglutide (mean difference = -0.25; % CI [-0.42; -0.07], p < 0.005).
• Morbidity – Weight loss
  • Furthermore, weight loss (mean difference = -3.31; % CI [-4.17; -2.45]; p < 0.001) was observed. However, the significance or impact of the observed weight loss over the long term, particularly with regard to cardiovascular safety, remains unclear.
• Health-related quality of life
  • There was no adequate validation for the target population regarding the assessment tools used in the AWARD-4 study (EQ-5D, APPADL/IW-SP and LBSS).
  • Consequently, no usable data on quality of life are available from the AWARD-4 study.
• Side effects – severe adverse events (SAEs)
  • 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 (RR = 0.50; 95% CI [0.33; 0.77]; p = 0.001).
• Side effects – discontinuation due to adverse events (AEs)
  • Treatment with dulaglutide + insulin lispro, with or without metformin, resulted in a statistically significantly higher proportion of patients discontinuing treatment due to AEs compared with combination therapy with insulin glargine + insulin lispro, with or without metformin, for the period up to week 52 (31 (10.5%) vs. 9 (3%); RR = 3.46; 95% CI [1.67; 7.13]; p < 0.001).
  • Nausea and dyspnoea from the SOC ‘Gastrointestinal disorders’ were the most common reasons for discontinuation due to AEs in the dulaglutide arm (8 and 3 patients, respectively), with an overall rate of 31 patients (10.5 %).
  • Overall, dulaglutide + insulin lispro, with or without metformin, resulted in a higher incidence of AEs leading to discontinuation compared with the appropriate comparator therapy (metformin + human insulin).
• Side effects – Symptomatic hypoglycaemia (blood glucose < 54 mg/dl and blood glucose ≤ 70 mg/dl)
  • For the endpoints relating to symptomatic hypoglycaemia with blood glucose cut-off values of < 54 mg/dl and ≤ 70 mg/dl, there was no statistically significant difference between the treatment groups for the period up to week 52.
  • It cannot therefore be concluded that dulaglutide + insulin lispro, with or without metformin, causes greater or minor harm compared with the appropriate comparator therapy (metformin + human insulin).
• Side effects – severe hypoglycaemia
  • In the operationalisation of severe hypoglycaemia, the pharmaceutical manufacturer includes the criterion of requiring external assistance in the dossier, in line with the definition of the American Diabetes Association (ADA) used as the operationalisation in the study report.
  • This operationalisation does not ensure that only severe hypoglycaemia is recorded. Consequently, no usable data were available for this endpoint.
• Overall review
  • In the overall assessment 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 AE, gastrointestinal disorders, nausea, diarrhoea, vomiting, dyspepsia and loss of appetite do not entirely call into question the advantage of dulaglutide in terms of SAE.
  • Nevertheless, they do diminish the advantage, resulting in a minor additional benefit of dulaglutide plus a short-acting insulin, with or without metformin, compared with the appropriate comparator therapy of metformin plus human insulin.

Courtesy translation only, please refer to the German original.