Saxagliptin / Metformin (1) – Komboglyze®

• Clinical trials
  • The G-BA therefore bases its assessment of the additional benefit on the randomised, double-blind Phase III trial D1680C00001, which investigated the combination of saxagliptin/metformin in comparison with glipizide/metformin.
  • In the dossier for the benefit assessment pursuant to Section 35a of the German Social Code, Book V (SGB V), the pharmaceutical manufacturer submitted a directly comparative, randomised, double-blind Phase IIIb trial (Study CV181057) to demonstrate the additional benefit of saxagliptin plus metformin in combination with insulin compared with metformin plus human insulin.

a) Dual combination therapy with saxagliptin and metformin in adult patients aged 18 years and over who are not adequately controlled on the maximum tolerated dose of metformin alone

• For patients treated with a dual combination therapy consisting of saxagliptin plus metformin who are not adequately controlled with the maximum tolerated dose of metformin alone, there is a hint of a minor additional benefit.
• The G-BA classifies the extent of the additional benefit of saxagliptin/metformin as minor, based on the criteria set out 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.
• Compared with the appropriate comparator therapy of sulphonylurea (glibenclamide or glimepiride) or glipizide, in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a moderate—and not merely minor—improvement in treatment-related benefit that has not previously been achieved, as a significant reduction in side effects (hypoglycaemia) is achieved.
• The certainty of the finding (probability of additional benefit) is classified in the ‘hint’ category.
• Based on these considerations, the information in the dossier, the results of the benefit assessment and the expert opinions, the G-BA establishes a hint of a minor additional benefit of saxagliptin in fixed dual combination therapy with metformin in adult patients aged 18 years and over, whose condition is not adequately controlled with the maximum tolerated dose of metformin alone, compared with a sulphonylurea (glimepiride or glipizide).
• mortality
  • The findings on mortality or cerebrovascular events are derived from the data on adverse events. In the overall population, no differences were observed between the treatment groups. No data were available for the target population.
• Morbidity – HbA1c (surrogate endpoint)
  • The primary endpoint selected in the study, HbA1c (change in HbA1c from baseline to week 52 and week 104 for study D1680C00001), represents a surrogate parameter in the treatment of diabetes mellitus.
  • In its public assessment report, the EMA concludes that saxagliptin/metformin is non-inferior to glipizide/metformin in terms of blood glucose reduction. The two treatments are therefore comparable with regard to the long-term blood glucose reduction targeted in the treatment of diabetes mellitus.
  • The primary endpoint of study D1680L00002 was to demonstrate the superiority of saxagliptin/metformin in achieving an HbA1c target of < 7% without confirmed or severe hypoglycaemia, compared with glimepiride/metformin. HbA1c < 7% without confirmed or severe hypoglycaemia was achieved by 37.9% of patients in the saxagliptin/metformin group and 38.2% in the glimepiride/metformin group. The difference was not statistically significant.
  • After 52 weeks, the difference in HbA1c reduction between the two groups was 0.18 (SE 0.075; 95% CI: [0.03; 0.33]).
• Side effects – hypoglycaemia
  • Confirmed symptomatic hypoglycaemia (blood glucose < 50 mg/dl) occurred statistically significantly less frequently in the saxagliptin/metformin arm compared with the glipizide/metformin arm (0 vs. 23; Peto OR: 0.12; 95% CI: [0.05; 0.27]; p < 0.001). 10 of the 13 episodes of hypoglycaemia observed up to week 6 occurred by week 3 – that is, whilst patients were on the minimum dose of glipizide.
  • The course of severe hypoglycaemia could not be deduced from the data provided, as the operationalisation used in study D1680C00001 was not suitable for capturing only serious cases of hypoglycaemia.
  • Severe hypoglycaemic episodes are, in principle, to be regarded as serious side effects. The G-BA therefore assumes, based on the avoidance of confirmed symptomatic hypoglycaemic episodes, that there is only a relevant reduction in side effects overall compared with glipizide.
  • In the study, confirmed symptomatic hypoglycaemia (blood glucose < 50 mg/dl) occurred statistically significantly less frequently overall with saxagliptin/metformin compared with glimepiride/metformin (1 (0.5%) vs. 19 (11.1%), Peto OR: 0.13; 95% CI: [0.05; 0.33]; p < 0.001). These episodes of hypoglycaemia occurred even at the lowest dose of glimepiride.
  • No data on severe hypoglycaemia were available for the target population. Severe hypoglycaemia is generally to be regarded as a serious side effect. The G-BA therefore concludes that, based on the avoidance of confirmed symptomatic hypoglycaemic episodes, there is only a relevant reduction in side effects overall compared with the appropriate comparator therapy.
• Side effects – weight gain
  • In the saxagliptin/metformin arm, a statistically significantly lower number of patients experienced weight gain of at least 7% compared with the glipizide/metformin arm (2 vs. 17; Peto OR: 0.18; 95% CI: [0.07; 0.45]; p < 0.001).
  • With regard to the endpoint of weight gain of at least 7%, there were no statistically significant differences between the groups.
• Health-related quality of life
  • Data on health-related quality of life were not collected in study D1680C00001. It is therefore not possible to draw any conclusions regarding an improvement or deterioration in quality of life with saxagliptin compared with glipizide.
  • With regard to quality of life, data (EQ-5D questionnaire) are available only for the overall population, but not for the target population relevant to this assessment.
• Overall assessment
  • An overall assessment of the results of both studies reveals no significant improvement in treatment-related benefit compared with the appropriate comparator therapy that has not previously been achieved; in particular, there is no alleviation of serious symptoms, no moderate prolongation of life, no relief perceptible to the patient, and no relevant prevention of serious side effects or a significant reduction in other side effects.
  • Therefore, classification as considerable additional benefit is not justified. The results regarding side effects (relevant prevention of confirmed, non-severe hypoglycaemia) are assessed as a moderate improvement in benefit not previously achieved compared with the appropriate comparator therapy.

b) Triple combination therapy with saxagliptin/metformin + insulin

• For patients treated with a triple combination therapy of saxagliptin/metformin + human insulin, in whom diet and exercise, as well as metformin and insulin alone, are insufficient for blood glucose control, the additional benefit is not proven.
• Overall, therefore, there is no additional benefit of saxagliptin plus metformin in combination with insulin compared with the appropriate comparator therapy (metformin + human insulin or, where appropriate, human insulin alone).
• mortality
  • No data were provided on mortality (all-cause mortality).
• Morbidity – HbA1c (surrogate parameter)
  • The primary endpoint of the study was the change in HbA1c levels from the start of the study to week 24 and to week 52; secondary endpoints were the change in the mean daily dose of insulin up to week 24, change in body weight, hypoglycaemic episodes and adverse events.
  • The primary endpoint of HbA1c selected in the study represents a surrogate parameter in the treatment of diabetes mellitus, as do other endpoints such as the change in daily insulin dose.
• Health-related quality of life
  • No data were presented on quality of life either. Consequently, it is not possible to draw any conclusions regarding an improvement or deterioration in quality of life with saxagliptin/metformin in combination with insulin compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.