Dapagliflozin (3) – Forxiga®
Diabetes mellitus type 1
Characteristics
| Start date | 01.05.2019 – Marketing authorisation: 20.03.2019 |
|---|---|
| Resolution | 17.10.2019 repealed |
| INN | Dapagliflozin |
| Brand name | Forxiga® |
| Pharm. company | AstraZeneca GmbH |
| G-BA Procedure ID | D-454 |
| ATC code | A10BK01 SGLT2 inhibitors (A10BK) |
| DDD | 10 mg O |
| Therapeutic area | Metabolic diseases Diabetes mellitus (DM type 1-2) |
| Reason for procedure | New therapeutic indication |
| Regulatory status | authorisation withdrawn by manufacturer |
| Therapeutic indication of the resolution |
|---|
|
Forxiga is indicated in adults for the treatment of insufficiently controlled type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy. |
| Subpopulation | Indication | Comparator |
|---|---|---|
| Adult patients with inadequately controlled type 1 diabetes mellitus and a BMI ≥27 kg/m2 whose blood glucose is not adequately controlled despite optimal insulin therapy | Human insulin or insulin analogues (insulin detemir, insulin glargin, insulin aspart, insulin glulisin, insulin lispro) |
Studies and Results
|
No. of studies
(best subpopulation) |
2 (DEPICT 1, DEPICT 2) |
|---|---|
|
Study design
(best subpopulation) |
H2H vs. ACT |
|
Meta analysis
(best subpopulation) |
yes |
- Clinical trials
- The DEPICT 1 and DEPICT 2 studies were submitted for the benefit assessment of dapagliflozin in type 1 diabetes mellitus.
- Both studies have an identical study design (twin studies) and are described together below. The studies were double-blind, parallel, randomised, placebo-controlled and multicentre.
- The aim of the studies was to investigate the efficacy and safety of dapagliflozin compared with placebo as an add-on therapy to insulin.
Adult patients with inadequately controlled type 1 diabetes mellitus and a BMI ≥27 kg/m<sup>2</sup>, whose blood glucose is not adequately controlled despite optimal insulin therapy
- mortality
- In both studies, no deaths occurred after 52 weeks. There was therefore no statistically significant difference between the treatment arms for the endpoint of all-cause mortality.
- Morbidity – HbA1c level
- Two different operationalisations of the HbA1c value are presented in the dossier. For the change in HbA1c level compared with baseline, the meta-analysis reveals a statistically significant advantage in favour of dapagliflozin and insulin compared with placebo and insulin (MD −0.33 % [−0.47; −0.19]; p < 0.001).
- For the responder analysis (HbA1c reduction ≥ 0.5 %; RR 1.92 [1.48; 2.50]; p < 0.001), the meta-analysis revealed a statistically significant advantage for dapagliflozin and insulin compared with placebo and insulin.
- When considering the mean change in HbA1c levels, an irrelevant between-group difference cannot be ruled out, as the 95% CI for the effect does not lie entirely outside the commonly used relevance threshold of 0.3 percentage points; the direction of the effect is consistent with the results of the responder analysis. Overall, for the endpoint HbA1c (as a sufficiently valid surrogate endpoint for microvascular complications), there is an additional benefit of dapagliflozin and insulin compared with insulin.
- Morbidity – Health status (EQ-5D VAS)
- For the health status endpoint, measured using the EQ-5D VAS, the meta-analysis reveals a statistically significant advantage for dapagliflozin and insulin compared with placebo and insulin. However, the 95% CI of the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range of −0.2 to 0.2. It is therefore not possible to conclude with sufficient certainty that the observed effect is clinically relevant.
- Morbidity – Hypoglycaemia Fear Survey (HFS-II) (Worry Subscale)
- The HFS-II (Worry Subscale) endpoint was only assessed in the DEPICT 2 study. The study showed no statistically significant difference between the treatment arms.
- quality of life
- In the DEPICT 1 and DEPICT 2 studies, no endpoints in the health-related quality of life category were investigated.
- Side effects – serious adverse events (SUEs)
- For the SAE endpoint, the meta-analysis showed no statistically significant difference between dapagliflozin and insulin compared with placebo and insulin.
- Side effects – discontinuation due to adverse events (AEs)
- The dossier contained contradictory analyses regarding the endpoint ‘discontinuation due to AEs’, which could only be addressed once further information had been submitted during the commenting procedure. The meta-analysis showed no statistically significant differences between dapagliflozin and insulin compared with placebo and insulin in either case.
- Side effects – symptomatic, confirmed hypoglycaemia
- In the meta-analysis for symptomatic, confirmed hypoglycaemia (plasma glucose ≤ 70 mg/dl), including patients who were incorrectly randomised, a statistically significant disadvantage was observed compared to dapagliflozin and insulin. The sensitivity analysis in the addendum (excluding incorrectly randomised patients) also shows a statistically significant result. However, for symptomatic, confirmed hypoglycaemia (plasma glucose ≤ 54 mg/dl), no statistically significant result was observed either in favour of or as a disadvantage of dapagliflozin.
- Overall, no adverse effect can be inferred from the results for this endpoint.
- Side effects – severe hypoglycaemia
- For the endpoint of severe hypoglycaemia (cases requiring medical treatment or treated with a glucagon injection or intravenous glucose), no statistically significant advantage or disadvantage was observed for dapagliflozin.
- Side effects – serious hypoglycaemia
- For the endpoint of serious hypoglycaemia (PT, SAE), the meta-analysis showed no statistically significant difference between dapagliflozin and insulin compared with placebo and insulin.
- Side effects – diabetic ketoacidosis
- For the endpoint of diabetic ketoacidosis (subdivided into possible and possible + confirmed cases), the meta-analysis showed no statistically significant difference between dapagliflozin and insulin compared with placebo and insulin in either case.
- Side effects – genital infections and gastrointestinal disorders
- For the endpoints of genital infections and gastrointestinal disorders (SOC, AE), the meta-analysis showed a statistically significant difference in each case to the disadvantage of dapagliflozin and insulin compared with placebo and insulin.
- Side effects – urinary tract infections
- For the endpoint of urinary tract infections, the meta-analysis showed no statistically significant difference between dapagliflozin and insulin compared with placebo and insulin.
- Overall review
- For dapagliflozin, a statistically significant advantage was observed in the morbidity category for the endpoint ‘extent of blood glucose control’, based on the results for HbA1c levels, which were assessed using two different operationalisations. A statistically significant advantage was observed in the change in HbA1c levels as well as in the responder analyses (HbA1c reduction of ≥ 0.5 percentage points).
- For the endpoint of symptomatic, confirmed hypoglycaemia, there was a disadvantage compared to dapagliflozin at the blood glucose threshold of ≤ 70 mg/dl. However, for symptomatic, confirmed hypoglycaemic episodes (plasma glucose ≤ 54 mg/dl), no disadvantage of dapagliflozin was observed. Overall, no negative effect can be inferred from the results for this endpoint.
- For the endpoints of genital infections and gastrointestinal disorders (SOC, AE), there was a statistically significant difference in favor of dapagliflozin compared with the control arm in each case.
- No statistically significant differences were observed for the other endpoints assessed.
- In the overall assessment of the study results, the positive effect of dapagliflozin on reducing the valid surrogate endpoint HbA1coverweighs the disadvantages in terms of side effects; consequently, a minor additional benefit is identified for dapagliflozin compared with the appropriate comparator therapy.
Courtesy translation only, please refer to the German original.
Associated procedures
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