Saxagliptin (1) – Onglyza®

• Clinical trials
  • Study D1680L00002 is a 52-week, direct-comparison, randomised, double-blind Phase III trial involving exclusively elderly patients (aged ≥ 65 years) who were not adequately controlled on metformin monotherapy.
  • The directly comparative, randomised, double-blind study D1680C00001 investigated adult patients with type 2 diabetes mellitus who had not achieved adequate blood glucose control despite metformin monotherapy at a daily dose of ≥ 1500 mg.

a) Dual combination therapy with saxagliptin and metformin, where metformin monotherapy does not adequately control blood glucose

• 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 plus metformin 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 treating the condition.
• The certainty of the finding (probability of additional benefit) is classified in the ‘hint’ category.
• mortality
  • The results on overall mortality and on cardiovascular or cerebrovascular events in studies D1680C00001 and D1680L00002 are derived from the data on adverse events. In the overall population, no differences were observed between the treatment groups.
• morbidity
  • The primary endpoint selected in study D1680C00001, HbA1c (change in HbA1c level compared with baseline at the start of the study at week 52 and week 104 for study D1680C00001) is a surrogate parameter in the treatment of diabetes mellitus.
  • In its public assessment report, the EMA concludes that saxagliptin plus metformin is non-inferior to glipizide plus metformin in terms of blood glucose reduction.
  • The primary endpoint of study D1680L00002 was to demonstrate the superiority of saxagliptin plus metformin in achieving an HbA1c target of < 7% without confirmed or severe hypoglycaemia, compared with glimepiride plus metformin. The difference between the two groups (37.9% for saxagliptin and 38.2% for glimepiride) was not statistically significant.
  • When considering the population aged < 75 years, 39.7% of patients in the saxagliptin plus metformin group achieved an HbA1c < 7% without hypoglycaemia, compared with 28.2% in the glimepiride plus metformin group (OR: 1.68; 95% CI: [1.09; 2.58]), although no statistically significant difference was observed in the extent of blood glucose reduction.
  • In the population aged ≥ 75 years, there was no statistically significant difference with regard to the criterion ‘achieving an HbA1c < 7% without hypoglycaemia’. After 52 weeks, the difference in HbA1c reduction between the two groups was 0.2 (SE 0.054; 95% CI: [0.09; 0.30]).
• 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.
  • In study D1680L00002, data were collected using the EQ-5D questionnaire to measure quality of life. The results for this endpoint are not analysed further in the pharmaceutical manufacturer’s dossier. The study data revealed a statistically significant difference in mean scores to the detriment of saxagliptin (-1 [-1.1; -0.9], p < 0.0001). The standardised mean difference, expressed as Hedges’ g, used to assess the clinical relevance of the statistically significant between-group difference (Hedges’ g: -0.061 [-0.214, 0.092]), indicated a non-clinically relevant between-group difference.
• Side effects
  • In study D1680C00001, confirmed symptomatic hypoglycaemia (blood glucose < 50 mg/dl) occurred statistically significantly less frequently in the saxagliptin plus metformin arm compared with the glipizide plus metformin arm (1 vs. 36; Peto OR: 0.14; 95% CI: [0.07; 0.26]; p < 0.001).
  • The incidence of serious hypoglycaemia could not be determined from the data provided, as the operationalisation used in study D1680C00001 was not suitable for capturing only serious cases of hypoglycaemia.
  • In study D1680L00002, confirmed symptomatic hypoglycaemia (blood glucose < 50 mg/dl) occurred statistically significantly less frequently overall with saxagliptin plus metformin compared with glimepiride plus metformin (1 (0.3%) vs. 36 (10.0%), Peto OR: 0.14; 95% CI: [0.07; 0.26]; p < 0.001).
  • There were no statistically significant differences in the incidence of severe hypoglycaemia between the saxagliptin plus metformin arm and the glimepiride plus metformin arm (1 (0.3%) vs. 6 (1.7%), Peto OR: 0.24; 95% CI: [0.05; 1.05]; p = 0.061).
  • In the saxagliptin plus metformin arm of study D1680C00001, a statistically significant smaller number of patients experienced a weight gain of at least 7% compared with the glipizide/metformin arm (6 vs. 37; RR: 0.16; 95% CI: [0.07; 0.38]; p < 0.001).
  • In study D1680L00002, there were no statistically significant differences between the groups with regard to the endpoint of weight gain of at least 7%.
• Overall assessment
  • An overall analysis of the results of both studies shows that, compared with the appropriate comparator therapy, there is no significant improvement in treatment-related benefit that has not previously been achieved; in particular, there is no alleviation of serious symptoms, no moderate prolongation of survival, no relief perceptible to the patient, and no relevant prevention of serious side effects or a significant reduction in other side effects.
  • The results regarding side effects (relevant reduction in confirmed, non-severe hypoglycaemia) are assessed as a moderate improvement in benefit compared with the appropriate comparator therapy, which has not been achieved to date.

Dual combination of saxagliptin with a sulphonylurea, where the use of metformin appears unsuitable and where sulphonylurea monotherapy does not adequately control blood glucose

• Side effects
  • As no relevant direct comparative study of saxagliptin in combination with a sulphonylurea against the appropriate comparator therapy of human insulin plus a sulphonylurea (glibenclamide or glimepiride) or human insulin alone, the pharmaceutical manufacturer is carrying out an adjusted indirect comparison.
• Overall assessment
  • Taken together, there were therefore no relevant data available for an indirect comparison to assess the additional benefit of saxagliptin in combination with a sulphonylurea compared with the appropriate comparator therapy of human insulin plus a sulphonylurea (glibenclamide or glimepiride) or human insulin alone.

Oral triple combination of saxagliptin with metformin and a sulphonylurea, if treatment with metformin and a sulphonylurea alone does not adequately control blood glucose

• For patients being treated with a triple combination therapy of saxagliptin, metformin and a sulphonylurea (i.e. as triple combination therapy) in addition to diet and exercise, where the maximum tolerated dose of both metformin and the sulphonylurea does not adequately control blood glucose, the additional benefit is not proven.
• Side effects
  • As there is no relevant direct comparative study of saxagliptin in combination with metformin and a sulphonylurea against the appropriate comparator therapy—human insulin in combination with metformin—the pharmaceutical manufacturer is conducting an adjusted indirect comparison.
• Overall assessment
  • Taken together, there were therefore no relevant data available for an indirect comparison to assess the additional benefit of saxagliptin plus metformin plus a sulphonylurea compared with the appropriate comparator therapy.

Combination of saxagliptin with insulin (with or without metformin), where treatment with insulin (with or without metformin) alone does not adequately control blood glucose

• For patients treated with a triple combination therapy of saxagliptin plus metformin plus 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.
• morbidity
  • The primary endpoint selected in the study, HbA1c, is a surrogate parameter in the treatment of diabetes mellitus, as are other endpoints such as, for example, changes in the daily insulin dose.
• mortality
  • No data were presented on mortality (all-cause mortality).
• 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 plus metformin in combination with insulin compared with the appropriate comparator therapy.
• Side effects
  • The data provided on cardiac events (as part of the study’s adverse event reporting) are not sufficient to assess any additional benefit, as the study was not designed to validly collect such data over the long term.
• Overall assessment
  • In its summary assessment of the described (methodological) shortcomings in the data presented for this patient group, the G-BA concludes that, for saxagliptin in combination with insulin and metformin or with insulin alone, this treatment alone, in conjunction with diet and exercise, does not adequately control blood glucose levels; no additional benefit has been established compared with the appropriate comparator therapy (metformin + human insulin or human insulin alone).

Courtesy translation only, please refer to the German original.