Semaglutid (Rybelsus, Ozempic, 1) – Rybelsus, Ozempic®, Rybelsus®

• Clinical trials
  • The SUSTAIN 6 trial was a randomised, placebo-controlled, double-blind trial conducted at multiple centres in North America, Latin America, Europe and Asia, as well as in Algeria, Australia, Israel and Turkey.
  • The PIONEER 6 trial is a randomised, placebo-controlled, double-blind trial that was conducted as a multicentre study in North and South America, Europe, Asia and Africa.

a1) 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 – in patients without manifest cardiovascular disease

• The additional benefit is not proven.

a2) 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 – in patients with manifest cardiovascular disease in combination with other medication to treat cardiovascular risk factors

• An additional benefit is not proven.
• In the SUSTAIN 6 and PIONEER 6 studies submitted for an assessment of additional benefit in patients with manifest cardiovascular disease in combination with other medication to treat cardiovascular risk factors (see comments on cross-patient aspects and on the studies, p. 11 ff), the proportion of patients not taking antidiabetic medication prior to the start of the study was less than 2 per cent. Furthermore, it is unclear to what extent this applies to these patients, or what proportion of patients met the inclusion criterion of ‘metformin intolerance or contraindication’.

b1) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with a blood-glucose-lowering medicinal product (other than insulin) do not adequately control blood glucose levels – in patients without manifest cardiovascular disease

• The additional benefit is not proven.
• Overall, it is concluded that there is no additional benefit of semaglutide + metformin compared with the appropriate comparator therapy, empagliflozin + metformin, in patient population b1) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with a blood glucose-lowering medicinal product (other than insulin) are not proven to adequately control blood glucose levels and who do not have manifest cardiovascular disease.
• mortality
  • Only one death occurred in the empagliflozin arm in the PIONEER 2 study. There were no significant differences between the treatment groups.
• Morbidity – acute coronary syndrome
  • In the PIONEER 2 study, acute coronary syndrome was defined as acute myocardial infarction, silent myocardial infarction or hospitalisation due to unstable angina pectoris; however, for silent myocardial infarctions and hospitalisations due to unstable angina pectoris, it remains unclear to what extent the results are influenced by incidental findings without symptoms or by the context of care. The dossier contains no information on the number of patients experiencing the individual events within the acute coronary syndrome component. Against this background, no usable data are available for the endpoint ‘acute coronary syndrome’.
• Morbidity – cerebrovascular event
  • In the PIONEER 2 study, the endpoint ‘cerebrovascular event’ comprises the following adjudicated events: ischaemic or haemorrhagic stroke, stroke of unknown aetiology, or TIA. Only four patients in the empagliflozin arm suffered a cerebrovascular event; whilst the difference is statistically significant in favour of semaglutide, no advantage can be inferred due to the minor number of events.
• Morbidity – hospitalisations due to heart failure, kidney disease and diabetic retinopathy
  • For the endpoints ‘hospitalisations due to heart failure’ and ‘kidney disease’, only a few events occurred (a maximum of 2 per study arm). There were no significant differences between the treatment groups.
  • With regard to the endpoint ‘diabetic retinopathy’, no usable data are available, as the PIONEER 2 study did not specifically assess diabetic retinopathy.
• Quality of life – SF-36v2
  • In the PIONEER 2 study, with a response threshold of 15% of the scale range for the physical and mental health summary scores, respectively, there was no statistically significant difference between the treatment groups in the SF-36 results.
• Side effects – Serious adverse events (SAEs)
  • SAE occurred in 6.8% of patients in the semaglutide arm and 9% in the empagliflozin arm. There were no statistically significant differences between the treatment groups.
• Side effects – Therapy discontinuation due to AEs
  • In the PIONEER 2 study, a statistically significant higher proportion of patients discontinued treatment due to AEs in the semaglutide arm compared with the empagliflozin arm (approximately 10.7% vs. 4.4%).
• Side effects – hypoglycaemia
  • For the endpoints ‘severe hypoglycaemia’ and ‘confirmed symptomatic hypoglycaemia (blood glucose ≤ 56 mg/dl)’, no statistically significant differences were observed between the treatment arms in the PIONEER 2 study.
  • No data are available in the dossier for the endpoint “symptomatic hypoglycaemia (blood glucose < 70 mg/dl)”. The pharmaceutical manufacturer is submitting this information with its written statement, which shows that in both study arms, 5.4% of patients experienced symptomatic hypoglycaemia (blood glucose < 70 mg/dl).
• Side effects – acute pancreatitis
  • In the PIONEER 2 study, acute pancreatitis occurred in only one patient in each of the two study arms; there is no statistically significant difference between the treatment groups.
• Side effects – Other specific AEs
  • In the PIONEER 2 study, more patients in the semaglutide arm experienced gastrointestinal disorders (SOC; 40.7% vs. 14.2%) and nausea (PT; 19.8% vs. 2.4%) compared with the empagliflozin arm. The result is statistically significant to the detriment of semaglutide.
  • With regard to genital infections, a statistically significant higher number of events were recorded in the empagliflozin arm (1.0% vs. 7.6%), whilst urinary tract infections occurred with similar frequency in both study arms (approx. 3%). Only one patient in the empagliflozin arm developed diabetic ketoacidosis. There were no statistically significant differences between the treatment groups for the endpoints of urinary tract infection and diabetic ketoacidosis.
• Overall assessment
  • Overall, only a few events relating to the endpoints of mortality and morbidity occurred in the study. Although there was a statistically significant advantage for semaglutide in terms of the endpoint ‘cerebrovascular events’ (0 vs. 4 events), no advantage is inferred due to the minor number of events. With regard to quality of life, semaglutide showed neither advantages nor disadvantages.
  • In the PIONEER 2 study, a statistically significant higher number of patients discontinued treatment due to AEs in the semaglutide arm compared with the empagliflozin arm, and there were disadvantages associated with semaglutide for the endpoints ‘gastrointestinal disorders’ and ‘nausea’, whereas advantages were observed with semaglutide compared with empagliflozin for the endpoint ‘genital infections’. The other adverse event endpoints showed no advantages or disadvantages associated with semaglutide compared with empagliflozin.

b2) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with a blood glucose-lowering medicinal product (other than insulin) do not adequately control blood glucose - in patients with established cardiovascular disease, in combination with other medication to treat cardiovascular risk factors

• An additional benefit is not proven.
• See the discussion on cross-patient aspects and on the PIONEER 6 and SUSTAIN 6 studies, p. 11 ff.
• Overall review
  • The overall review of the results from the PIONEER 6 and SUSTAIN 6 studies reveals both advantages and disadvantages of semaglutide compared with the control group. The advantages observed in the PIONEER 6 study with regard to all-cause mortality and cardiovascular mortality, and in the SUSTAIN 6 study for the endpoint MACE and non-fatal strokes, could not be confirmed by the results of the other study. The results unfavourable to semaglutide regarding therapy discontinuations due to AEs (adverse events) involving the gastrointestinal tract are evident in both studies; further disadvantages relating to retinal photocoagulation and gastrointestinal disorders were observed only in the SUSTAIN 6 study, although these endpoints were not assessed in the PIONEER 6 study.
  • Given the heterogeneous results of the two studies, the minor extent and questionable validity of the observed effects in the mortality and morbidity endpoint categories, as well as the clear disadvantages regarding side effects, and in light of the described, relevant uncertainties in the studies—particularly regarding their generalisability to the German healthcare context and the lack of comparison with the appropriate comparator therapy in the respective patient group—it is concluded, on balance, that the additional benefit of semaglutide is not proven.

c1) Adult patients with type 2 diabetes mellitus in whom diet and exercise, together with treatment with at least two blood glucose-lowering medicinal products (excluding insulin), do not adequately control blood glucose levels – in patients without manifest cardiovascular disease

• An additional benefit is not proven.

c2) 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 - in patients with manifest cardiovascular disease, in combination with further medication to treat cardiovascular risk factors

• The additional benefit is not proven.
• See the discussion on cross-patient aspects and on the PIONEER 6 and SUSTAIN 6 studies, p. 11 ff.
• Overall review
  • The overall review highlights both the advantages and disadvantages of semaglutide compared with the control group. The advantages regarding all-cause mortality and cardiovascular mortality (PIONEER 6), as well as the endpoints of MACE and non-fatal strokes (SUSTAIN 6), could not be confirmed by the results of the other study. The results unfavourable to semaglutide regarding therapy discontinuations due to AEs are evident in both studies; further disadvantages relating to retinal photocoagulation and gastrointestinal disorders are evident only in the SUSTAIN 6 study, although these were not assessed in the PIONEER 6 study.
  • Particularly in light of the ongoing development of antidiabetic therapy in accordance with current guideline recommendations, it would have been expected that patients would have been treated more frequently with liraglutide or empagliflozin as part of the standard therapy administered. Although adjustments to antidiabetic and antihypertensive therapy were made in both studies, it is generally assumed that further adjustments to antidiabetic and antihypertensive therapy in the control arm would have been necessary during the course of the studies in order to achieve the patients’ target values.
  • Given the heterogeneous results of the two studies, the minor extent and questionable validity of the observed effects on mortality and morbidity, as well as the significant disadvantages in terms of side effects, and in light of the described uncertainties in the studies—particularly regarding their generalisability to the German healthcare context and the lack of comparison with the appropriate comparator therapy—it has been concluded, on balance, that the additional benefit of semaglutide is not proven.

d1) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with insulin (with or without another blood glucose-lowering medicinal product) do not adequately control blood glucose levels – in patients without manifest cardiovascular disease

• An additional benefit is not proven.

d2) Adult patients with type 2 diabetes mellitus in whom diet, exercise and treatment with insulin (with or without another blood glucose-lowering medicinal product) do not adequately control blood glucose - in patients with manifest cardiovascular disease, in combination with other medication to treat cardiovascular risk factors

• The additional benefit is not proven.
• See the discussion on cross-patient aspects and on the PIONEER 6 and SUSTAIN 6 studies, p. 11 ff.
• Overall review
  • The overall review highlights both the advantages and disadvantages of semaglutide compared with the control group. The advantages regarding all-cause mortality and cardiovascular mortality (PIONEER 6), as well as the endpoints of MACE and non-fatal strokes (SUSTAIN 6), could not be confirmed by the results of the other study. The results unfavourable to semaglutide regarding therapy discontinuations due to AEs are evident in both studies; further disadvantages relating to retinal photocoagulation and gastrointestinal disorders are evident only in the SUSTAIN 6 study, although these were not assessed in the PIONEER 6 study.
  • Particularly in light of the ongoing development of antidiabetic therapy in accordance with current guideline recommendations, it would have been expected that patients would have been treated more frequently with liraglutide or empagliflozin as part of the standard therapy administered. Although adjustments to antidiabetic and antihypertensive therapy were made in both studies, it is generally assumed that further adjustments to antidiabetic and antihypertensive therapy in the control arm would have been necessary during the course of the studies in order to achieve the patients’ target values.
  • Given the heterogeneous results of the two studies, the minor extent and questionable validity of the observed effects on mortality and morbidity, as well as the significant disadvantages in terms of side effects, and in light of the described uncertainties in the studies—particularly regarding their generalisability to the German healthcare context and the lack of comparison with the appropriate comparator therapy—it is concluded, on balance, that the additional benefit of semaglutide is not proven.
• Mortality – all-cause mortality / cardiovascular mortality
  • In the SUSTAIN 6 study, there were no significant differences between the treatment groups in terms of all-cause mortality and the endpoint ‘cardiovascular death’.
  • Overall, in the PIONEER 6 study, there were 23 (1.4%) deaths in the semaglutide arm and 45 (2.8%) deaths in the control arm (all-cause mortality). With regard to the endpoint ‘cardiovascular death’, 15 (0.9%) deaths were recorded in the semaglutide arm and 30 (1.9%) deaths in the control arm. For both endpoints, the number of deaths in the semaglutide arm was statistically significantly lower than in the control arm.
• Morbidity – Combined endpoint: major adverse cardiovascular events (MACE)
  • In both studies, the composite endpoint ‘major adverse cardiovascular events (MACE)’ comprises the endpoints ‘cardiovascular death’, ‘non-fatal myocardial infarction’ and ‘non-fatal stroke’.
  • In the SUSTAIN 6 study, a statistically significant difference in favour of semaglutide was observed for MACE (HR 0.74, 95% CI [0.58; 0.95]; p=0.017). When considering the individual components, a statistically significant advantage for semaglutide was observed for the endpoint ‘non-fatal stroke’ (HR 0.61; 95% CI [0.38; 0.99]; p=0.04). For the other components, ‘non-fatal myocardial infarction’ and ‘cardiovascular death’, there were no statistically significant differences between the treatment arms.
  • In the PIONEER 6 study, the composite endpoint MACE cannot be interpreted, as the effects of semaglutide on the individual components are not consistent. The following results were observed for the individual components: With regard to the endpoint ‘cardiovascular death’, there was a statistically significant advantage for semaglutide. For the endpoint ‘non-fatal stroke’, numerically fewer strokes were observed in the semaglutide arm compared with the control arm (0.8% vs. 1.0%). With regard to the endpoint ‘non-fatal myocardial infarction’, more events occurred in the semaglutide arm compared with the control arm (2.3% vs. 1.9%). However, for both endpoints, there were no statistically significant differences between the treatment arms.
• Morbidity – other cardiovascular morbidity endpoints
  • For the endpoints comprising the total number of fatal and non-fatal myocardial infarctions, as well as strokes, hospitalisation due to heart failure and TIA, there were no statistically significant differences between the treatment groups in either study.
• Morbidity – complications of diabetic retinopathy
  • With regard to the endpoints relating to complications of diabetic retinopathy, the SUSTAIN 6 study showed a statistically significant disadvantage for semaglutide compared with the comparator arm for the endpoint ‘retinal photocoagulation’ (2.3% vs. 1.2%). For the other individual endpoints, ‘vitreous haemorrhage’ and ‘diabetes-related blindness’, only a few events occurred, and a trend favouring the comparator arm was observed for semaglutide; however, this was not statistically significant in either case.
  • In the PIONEER 6 study, the endpoint ‘diabetic retinopathy’ was not systematically recorded; consequently, no usable data are available for the benefit assessment.
• Morbidity – kidney disease
  • In the SUSTAIN 6 study, there were no statistically significant differences between the semaglutide arm and the comparator arm with regard to the endpoints ‘acute kidney injury’, ‘kidney failure’ and ‘initiation of long-term renal replacement therapy’.
  • For the endpoint ‘acute kidney injury’, the PIONEER 6 study showed no statistically significant differences between the treatment groups. The operational definitions of the endpoints ‘renal failure’ and ‘initiation of long-term renal replacement therapy’ were not recorded in the study; consequently, no usable data are available for the benefit assessment.
• Quality of life – SF-36v2
  • In the SUSTAIN 6 study, with a response threshold of 15% of the scale range for the physical and mental health summary scores, respectively, there was no statistically significant difference between the treatment groups with regard to the SF-36 results.
  • In the PIONEER 6 study, the quality of life endpoint was not assessed; consequently, no usable data are available for the benefit assessment.
• Side effects – Serious adverse events (SAE)
  • In the PIONEER 6 and SUSTAIN 6 studies, there were no statistically significant differences between the treatment groups for the SAE endpoint in either study.

Courtesy translation only, please refer to the German original.