Saxagliptin / Metformin (3) – Komboglyze®

• Clinical trials
  • Study D1680L00002 was a 52-week, directly comparative, randomised, double-blind Phase IIIstudy involving exclusively elderly patients (aged ≥ 65 years) who were inadequately controlled on metformin monotherapy (HbA1c ≥ 7.0% to ≤ 9.0%).
  • The directly comparative, randomised, double-blind Phase III study D1680C00001 investigated the combination of saxagliptin and metformin compared with glipizide and metformin.
  • The CV181057 study was designed to investigate the efficacy of saxagliptin in combination with insulin or insulin and metformin compared with insulin (or the combination of insulin plus metformin) and placebo.

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

• An additional benefit is not proven.
• Overall, no additional benefit has been demonstrated for the dual combination therapy of saxagliptin andmetformin in adult patients aged 18 years and over who are not adequately controlled on the maximum tolerated dose of metformin alone is not proven compared with the appropriate comparator therapy.
• mortality
  • The results regarding mortality or cerebrovascular events from the two studies D1680C00001 and D1680L00002 are derived from the data on adverse events. For the target population, study D1680L00002 showed no statistically significant differences. For study D1680C00001, no data were available for this population.
• morbidity
  • The results on mortality or cerebrovascular events from the two studies D1680C00001 and D1680L00002 are derived from the adverse event data.
• Health-related quality of life
  • Data on health-related quality of life were not collected in studies D1680C00001 and D1680L00002. It is therefore not possible to draw any conclusions regarding an improvement or deterioration in quality of life with saxagliptin/metformin compared with the appropriate comparator therapy.
• Side effects
  • The results for the endpoints ‘Serious adverse events (SAE)’ ‘pancreatitis’ and ‘renal dysfunction’ showed no statistically significant differences between the treatment groups for the target populations in either of the two studies D1680C00001 and D1680L00002.
  • 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 (10.4 %); Peto OR: 0.12; 95% CI: [0.05; 0.27]; p < 0.001).
  • In study D1680L00002, confirmed symptomatic hypoglycaemia (blood glucose < 50 mg/dl) occurred at a statistically significantly lower rate 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).
  • Therapy discontinuations due to AEs: In the saxagliptin/metformin arm of study D1680L00002, a statistically significant higher number of patients discontinued treatment due to an adverse event compared with the glipizide/metformin arm (11 (5.8%) vs. 3 (1.8%); RR: 3.30; 95% CI: [0.94; 11.63]; p = 0.049). However, this endpoint cannot be validly interpreted.
• Overall assessment
  • In the overall analysis of the results from the two studies, D1680C00001 and D1680L00002, the lower number of confirmed, non-severe hypoglycaemic episodes with saxagliptin/metformin, a moderate improvement compared with the appropriate comparator therapy.

b) Triple combination of saxagliptin/metformin with insulin as an adjunct to diet and exercise to improve glycaemic control in adult patients aged 18 years and over with type 2 diabetes mellitus, when insulin and metformin alone do not adequately control blood glucose

• The additional benefit is not proven.
• Overall, the G-BA concludes that for saxagliptin/metformin in combination with insulin as an adjunct to diet and exercise, where insulin and metformin alone do not adequately control blood glucose, no additional benefit has been established compared with the appropriate comparator therapy (metformin + human insulin or human insulin alone).
• mortality
  • No data were submitted regarding mortality (all-cause mortality).
• morbidity
  • The data submitted on cardiac events (as part of the study’s adverse event reporting) are not meaningful for the assessment of additional benefit, as the study submitted was not designed to validly collect these data over the long term.
• Health-related quality of life
  • No data were provided 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.
• Conclusion
  • In summary, due to the shortcomings described, the present study CV181057 is methodologically unsuitable for assessing the additional benefit of saxagliptin/metformin in combination with insulin.

Courtesy translation only, please refer to the German original.