Semaglutid (1) – Ozempic®

• Clinical trials
  • In its dossier, the pharmaceutical manufacturer submits the SUSTAIN 6 trial for the benefit assessment pursuant to Section 35a of the German Social Code, Book V (SGB V) for semaglutide in adult patients with type 2 diabetes mellitus as an adjunct to diet and physical activity, both for monotherapy and for combination therapy.
  • The SUSTAIN 6 trial is a randomised, placebo-controlled, double-blind study conducted on a multicentre basis in North America, Latin America, Europe and Asia, as well as in Algeria, Australia, Israel and Turkey.

a1) Adult patients with type 2 diabetes mellitus in whom diet and exercise alone do not adequately control blood glucose levels, and for whom the use of metformin is not suitable due to intolerance – in patients without manifest cardiovascular disease

• The additional benefit is not proven.
• No study has been submitted to assess the additional benefit of semaglutide monotherapy, where diet and exercise alone do not adequately control blood glucose levels in adult patients with type 2 diabetes mellitus without manifest cardiovascular disease, and where the use of metformin is considered unsuitable due to intolerance, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride).

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 unsuitable 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.
• No direct comparative studies have been presented that would allow an assessment of the additional benefit of semaglutide monotherapy, where diet and exercise alone do not adequately control blood glucose levels in adult patients with type 2 diabetes mellitus and manifest cardiovascular disease, and where the use of metformin is considered unsuitable due to intolerance, compared with the appropriate comparator therapy (sulfonylurea: glibenclamide or glimepiride in combination with other medication to treat cardiovascular risk factors).
• In the SUSTAIN 6 study submitted for an assessment of the additional benefit in patients with manifest cardiovascular disease in combination with other medication to treat cardiovascular risk factors (see discussion of cross-patient aspects and the study, p. 9 ff), only 1.4% of patients (corresponding to 23 study participants) in the intervention arm were treated with semaglutide without any further antidiabetic medication.

b1) treatment with a blood glucose-lowering medicinal product (other than insulin) – in patients without manifest cardiovascular disease

• The additional benefit is not proven.
• A search for directly comparable studies did not identify any relevant study on semaglutide in combination with another blood-glucose-lowering medicinal product other than insulin.

b2) treatment with a blood glucose-lowering medicinal product (other than insulin) – in patients with manifest cardiovascular disease in combination with further medication to treat cardiovascular risk factors

• Hint of a minor additional benefit.
• See the discussion on cross-patient aspects and on the study, p. 9 ff.
• mortality
  • There are no significant differences between the treatment groups with regard to overall mortality and the endpoint ‘cardiovascular death’.
• Morbidity – Major Adverse Cardiovascular Events (MACE)
  • The composite endpoint ‘major adverse cardiovascular events (MACE)’ comprises the endpoints of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
  • For the combined MACE endpoint, there was a statistically significant difference in favour of semaglutide (HR 0.74, 95% CI [0.58; 0.95]; p=0.017).
  • When considering the individual components, the ‘non-fatal stroke’ endpoint showed a statistically significant advantage for semaglutide (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.
• Morbidity – Complications of diabetic retinopathy (retinal photocoagulation)
  • Among the endpoints relating to complications of diabetic retinopathy, the endpoint ‘retinal photocoagulation’ showed a statistically significant disadvantage for semaglutide compared with the comparator arm (HR 1.91; 95% CI [1.11; 3.28]; p=0.019).
• Morbidity – Other morbidity endpoints
  • For the other endpoints assessed – the total number of fatal and non-fatal myocardial infarctions and strokes, hospitalisation due to heart failure, TIA, renal failure and the initiation of long-term renal replacement therapy, there were no statistically significant differences between the semaglutide arm and the comparator arm.
• Quality of life – SF-36 Mental Component Score
  • No statistically significant difference was observed between the treatment arms for the Mental Component Score (MCS) of the SF-36.
• Quality of life – SF-36 Physical Component Score
  • For the Physical Component Score (PCS) of the SF-36, a statistically significant difference in favour of semaglutide was observed in the change in scores from baseline to week 104 (MD 1.1; 95% CI [0.5; 1.6]; p < 0.001).
  • To assess the clinical relevance of this difference, the standardised mean difference (SMD 0.2; 95% CI [0.1; 0.2]) is used.
  • The confidence interval for the effect size does not lie within a range that can be considered definitively irrelevant. It cannot therefore be concluded that the effect can be regarded as clinically relevant.
• Side effects – therapy discontinuation due to adverse events
  • For the endpoints of therapy discontinuation due to AEs, SOC gastrointestinal disorders, and in the PT nausea, vomiting, diarrhoea and reduced appetite, there was a statistically significant difference to the detriment of semaglutide compared with the comparator arm in each case.
• Overall view
  • In the morbidity category, the combined cardiovascular endpoint ‘MACE’ showed a statistically significant advantage for semaglutide compared with the control group, which is attributable to the individual component ‘non-fatal strokes’.
  • By contrast, for the endpoints ‘retinal photocoagulation’, ‘therapy discontinuation due to AEs’ and ‘gastrointestinal disorders’, there was a statistically significant disadvantage compared with the control group for semaglutide.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the control arm, the study is, on the whole, subject to uncertainties.
  • Overall, there is a hint of a minor additional benefit of semaglutide compared with the appropriate comparator therapy in this patient group.

c1) treatment with at least two blood glucose-lowering medicinal products (excluding insulin) – in patients without manifest cardiovascular disease

• The additional benefit is not proven.
• There are no studies available to assess the additional benefit of semaglutide in combination therapy with at least two blood glucose-lowering medicinal products (excluding insulin) in adult patients with type 2 diabetes mellitus without high cardiovascular risk, where diet and exercise alone do not adequately control blood glucose, compared with the appropriate comparator therapy (human insulin in combination with metformin).

c2) treatment with at least two blood glucose-lowering medicinal products (excluding insulin) – in patients with established cardiovascular disease, in combination with further medication to treat cardiovascular risk factors

• Hint for a minor additional benefit.
• See the discussion on cross-patient aspects and on the study, p. 9 ff.
• mortality
  • There are no significant differences between the treatment groups with regard to overall mortality and the endpoint ‘cardiovascular death’.
• Morbidity – Major Adverse Cardiovascular Events (MACE)
  • The composite endpoint ‘major adverse cardiovascular events (MACE)’ comprises the endpoints of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
  • For the combined MACE endpoint, there was a statistically significant difference in favour of semaglutide (HR 0.74, 95% CI [0.58; 0.95]; p=0.017).
  • When considering the individual components, the ‘non-fatal stroke’ endpoint showed a statistically significant advantage for semaglutide (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.
• Morbidity – Complications of diabetic retinopathy (retinal photocoagulation)
  • Among the endpoints relating to complications of diabetic retinopathy, the endpoint ‘retinal photocoagulation’ showed a statistically significant disadvantage for semaglutide compared with the comparator arm (HR 1.91; 95% CI [1.11; 3.28]; p=0.019).
• Morbidity – Other morbidity endpoints
  • For the other endpoints assessed – the total number of fatal and non-fatal myocardial infarctions and strokes, hospitalisation due to heart failure, TIA, renal failure and initiation of long-term renal replacement therapy, there were no statistically significant differences between the semaglutide arm and the comparator arm.
• Quality of life – SF-36 Mental Component Score
  • No statistically significant difference was observed between the treatment arms for the Mental Component Score (MCS) of the SF-36.
• Quality of life – SF-36 Physical Component Score
  • For the Physical Component Score (PCS) of the SF-36, a statistically significant difference in favour of semaglutide was observed in the change in scores from baseline to week 104 (MD 1.1; 95% CI [0.5; 1.6]; p < 0.001).
  • To assess the clinical relevance of this difference, the standardised mean difference (SMD 0.2; 95% CI [0.1; 0.2]) is used.
  • The confidence interval for the effect size does not lie within a range that can be considered definitively irrelevant. It cannot therefore be concluded that the effect can be regarded as clinically relevant.
• Side effects – therapy discontinuation due to adverse events
  • For the endpoints of therapy discontinuation due to AEs, SOC gastrointestinal disorders, and in the PT nausea, vomiting, diarrhoea and reduced appetite, there was a statistically significant difference to the detriment of semaglutide compared with the comparator arm in each case.
• Overall view
  • In the morbidity category, the combined cardiovascular endpoint ‘MACE’ showed a statistically significant advantage for semaglutide compared with the control group, driven by the individual component ‘non-fatal strokes’.
  • By contrast, for the endpoints ‘retinal photocoagulation’, ‘therapy discontinuation due to AEs’ and ‘gastrointestinal disorders’, there was a statistically significant disadvantage compared with the control group for semaglutide.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the control arm, the study is, on the whole, subject to uncertainties.
  • Overall, there is a hint of a minor additional benefit of semaglutide compared with the appropriate comparator therapy in this patient group.

d1) treatment with insulin (with or without another blood glucose-lowering agent – in patients without manifest cardiovascular disease

• An additional benefit is not proven.
• There are no studies available to assess the additional benefit of semaglutide in combination therapy with insulin in adult patients with type 2 diabetes mellitus without high cardiovascular risk, where diet and exercise alone do not adequately control blood glucose, compared with the appropriate comparator therapy (optimisation of the human insulin regimen).

d2) treatment with insulin (with or without another blood glucose-lowering agent – in patients with manifest cardiovascular disease in combination with further medication to treat cardiovascular risk factors

• hint of a minor additional benefit.
• See the discussion on cross-patient aspects and on the study, p. 9 ff.
• mortality
  • There are no significant differences between the treatment groups with regard to overall mortality and the endpoint ‘cardiovascular death’.
• Morbidity – Major Adverse Cardiovascular Events (MACE)
  • The composite endpoint ‘major adverse cardiovascular events (MACE)’ comprises the endpoints of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
  • For the combined MACE endpoint, there was a statistically significant difference in favour of semaglutide (HR 0.74, 95% CI [0.58; 0.95]; p=0.017).
  • When considering the individual components, the ‘non-fatal stroke’ endpoint showed a statistically significant advantage for semaglutide (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.
• Morbidity – Complications of diabetic retinopathy (retinal photocoagulation)
  • Among the endpoints relating to complications of diabetic retinopathy, the endpoint ‘retinal photocoagulation’ showed a statistically significant disadvantage for semaglutide compared with the comparator arm (HR 1.91; 95% CI [1.11; 3.28]; p=0.019).
• Morbidity – Other morbidity endpoints
  • For the other endpoints assessed – the total number of fatal and non-fatal myocardial infarctions and strokes, hospitalisation due to heart failure, TIA, renal failure and initiation of long-term renal replacement therapy, there were no statistically significant differences between the semaglutide arm and the comparator arm.
• Quality of life – SF-36 Mental Component Score
  • No statistically significant difference was observed between the treatment arms for the Mental Component Score (MCS) of the SF-36.
• Quality of life – SF-36 Physical Component Score
  • For the Physical Component Score (PCS) of the SF-36, a statistically significant difference in favour of semaglutide was observed in the change in scores from baseline to week 104 (MD 1.1; 95% CI [0.5; 1.6]; p < 0.001).
  • To assess the clinical relevance of this difference, the standardised mean difference (SMD 0.2; 95% CI [0.1; 0.2]) is used.
  • The confidence interval for the effect size does not lie within a range that can be considered definitively irrelevant. It cannot therefore be concluded that the effect can be regarded as clinically relevant.
• Side effects – therapy discontinuation due to adverse events
  • For the endpoints of therapy discontinuation due to AEs, SOC gastrointestinal disorders, and in the PT nausea, vomiting, diarrhoea and reduced appetite, there was a statistically significant difference to the detriment of semaglutide compared with the comparator arm in each case.
• Overall view
  • In the morbidity category, the combined cardiovascular endpoint ‘MACE’ showed a statistically significant advantage for semaglutide compared with the control group, driven by the individual component ‘non-fatal strokes’.
  • By contrast, for the endpoints ‘retinal photocoagulation’, ‘therapy discontinuation due to AEs’ and ‘gastrointestinal disorders’, there was a statistically significant disadvantage compared with the control group for semaglutide.
  • Given that the intensification of treatment carried out could have been further optimised, particularly in the control arm, the study is, on the whole, subject to uncertainties.
  • On balance, there is a hint of a minor additional benefit of semaglutide compared with the appropriate comparator therapy in this patient group.

• Overall assessment
  • The SUSTAIN 6 study was submitted for the assessment of the additional benefit of semaglutide as monotherapy or in combination with other antidiabetic agents for the treatment of inadequately controlled type 2 diabetes mellitus in adults, as an adjunct to diet and exercise.
  • This study exclusively included patients with type 2 diabetes mellitus who had an HbA1c level of ≥ 7.0 % and either established cardiovascular disease from the age of 50 or a high risk of cardiovascular disease from the age of 60.
  • Around 83% of all patients in the study had confirmed manifest cardiovascular disease, whilst the remaining 17% of patients were at risk of cardiovascular disease.
  • Against this background, conclusions can only be drawn for patients with type 2 diabetes mellitus and manifest cardiovascular disease.
  • No studies are available for patients without manifest cardiovascular disease (patient groups a1, b1, c1 and d1).
  • The aim of the study was to demonstrate the cardiovascular safety of semaglutide, as measured by the composite endpoint of MACE: cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
  • No significant difference between the treatment arms was observed in the mortality category.
  • For the MACE endpoint, a statistically significant advantage of semaglutide over the control group was observed, which was due in particular to the individual component ‘non-fatal strokes’.
  • In contrast, a statistically significant disadvantage compared with the control group was observed for the retinal photocoagulation endpoint.
  • A statistically significant difference to the detriment of semaglutide compared with the control arm was also observed for the endpoints of therapy discontinuation due to AEs and gastrointestinal disorders.
  • No statistically significant differences were observed for the other endpoints.
  • Taking the study results as a whole, the advantage of semaglutide in the MACE endpoint—including the findings on non-fatal strokes—outweighs the findings unfavourable to semaglutide in retinal photocoagulation and adverse events.
  • The additional benefit is assessed as minor, taking the advantages and disadvantages into account.
  • For patients without manifest cardiovascular disease, the additional benefit is not proven.
• For the benefit assessment of semaglutide across the entire authorised therapeutic indication, only the SUSTAIN 6 study is available, which exclusively investigated patients with type 2 diabetes mellitus aged 50 years or over and with manifest cardiovascular disease.
• The study contains uncertainties that limit the validity of the results.
• Overall, therefore, the certainty of the evidence is classified in the ‘hint’ category.

Courtesy translation only, please refer to the German original.