Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin

Conditions

Type 2 Diabetes

Keywords

Dapagliflozin, efficacy, safety, add on to insulin, Oral AntiDiabetic, Type 2 diabetes

Brief summary

This study is being carried out to see if Dapagliflozin in addition to insulin is effective and safe in treating patients with type 2 diabetes when compared to placebo (identical looking inactive treatment) in addition to insulin

Jens Aberle, Markus Menzen, Sebastian Schmid, Christoph Terkamp, Elmar Jaeckel et al. (10 authors)

Scientific Reports2020-12-2844 citations

10.1038/s41598-020-78734-z

A model‐based approach to investigating the relationship between glucose‐insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes

Millie Shah, Leonid Stolbov, Tatiana A. Yakovleva, Weifeng Tang, Victor Sokolov et al. (8 authors)

Diabetes Obesity and Metabolism2020-12-248 citations

10.1111/dom.14305

Model‐based characterization of the relationship between dapagliflozin systemic exposure and HbA1c response in patients with type 1 diabetes mellitus

Joanna Parkinson, Weifeng Tang, Magnus Åstrand, Johanna Melin, Ella Ekholm et al. (7 authors)

Diabetes Obesity and Metabolism2019-02-139 citations

10.1111/dom.13664

Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis.

Mellander A, Billger M, Johnsson E, Träff AK, Yoshida S, Johnsson K.

2016-11-0114 citations

10.1007/s40261-016-0438-3

The effect of dapagliflozin on renal function in patients with type 2 diabetes

Donald E. Kohan, Paola Fioretto, Kristina Johnsson, Shamik Parikh, Agata Ptaszynska et al. (6 authors)

Journal of Nephrology2016-02-1977 citations

10.1007/s40620-016-0261-1

Cost effectiveness of adding dapagliflozin to insulin for the treatment of type 2 diabetes mellitus in the Netherlands.

van Haalen HG, Pompen M, Bergenheim K, McEwan P, Townsend R, Roudaut M.

2014-02-0134 citations

10.1007/s40261-013-0155-0

How many unpublished studies? ClinicalTrials.gov (n = 2614 studies): diabetes | Closed Studies | Interventional Studies | Phase 3, 4 | Search Date: Oct 27, 2014

Ramirez Jorge H

Figshare2014-01-01

10.6084/m9.figshare.1249628.v1

Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years.

Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S, Dapagliflozin 006 Study Group.

2013-08-29225 citations

10.1111/dom.12187

[Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin].

Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S, Studiengruppe Dapagliflozin 006.

2013-03-257 citations

10.1055/s-0032-1305284

Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.

Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S, Dapagliflozin 006 Study Group.

2012-03-01361 citations

10.7326/0003-4819-156-6-201203200-00003

Interventions

DRUGDapagliflozin

tablet oral 2.5 mg total daily dose once daily 48 weeks (= 24 week randomised treatment period + 24 week study extension period I)

DRUGPlacebo

Placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

No

Inclusion criteria

* Type 2 Diabetes * Patients with HbA1c ≥7.5% and ≤10.5% and who are on a stable insulin regimen of at least 30 IU of injectable insulin per day either without any other oral antidiabetic drug or with a stable dose of oral antidiabetic drugs

Exclusion criteria

* Type 1 Diabetes * Treatment with more than two additional oral antidiabetic drugs * Moderate and severe renal (kidney) failure or dysfunction

Design outcomes

Primary

Measure	Time frame	Description
Adjusted Mean Change in HbA1c Levels	Baseline to Week 24	To assess the efficacy of 2.5 mg, 5 mg and 10 mg dapagliflozin compared to placebo as add-on therapy to insulin in improving glycaemic control in participants with type 2 diabetes who have inadequate glycaemic control on ≥ 30 IU injectable insulin daily for at least 8 weeks prior to enrolment, as determined by the change in HbA1c levels from baseline to Week 24, excluding data after insulin up-titration.

Secondary

Measure	Time frame	Description
Adjusted Mean Change in Body Weight	Baseline to Week 24	To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing body weight or causing less weight gain as compared to placebo added to insulin treatment after 24 weeks of treatment (LOCF), excluding data after insulin up-titration.
Adjusted Mean Change in Calculated Mean Daily Insulin Dose	Baseline to Week 24	To examine whether treatment with dapagliflozin in combination with insulin leads to a lower absolute calculated mean daily insulin dose as compared to placebo added to insulin treatment alone, from baseline to week 24, including data after insulin up-titration.
Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	Baseline to Week 24	To examine whether treatment with dapagliflozin in combination with insulin leads to higher percentage of participants with calculated mean daily insulin dose reduction from baseline to week 24 (i.e. reduction \>= 10%) as compared to placebo added to insulin treatment.
Adjusted Mean Change in Fasting Plasma Glucose (FPG)	Baseline to Week 24	To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing Fasting Plasma Glucose (FPG) as compared to placebo added to insulin treatment after 24 weeks of treatment, excluding data after insulin up-titration.

Other

Measure	Time frame	Description
Proportion of Participants With Lack of Glycemic Control	Baseline to Week 24	Participants with lack of glycemic control or insulin up-titration for failing to achieve pre-specified glycemic targets

Countries

Austria, Bulgaria, Canada, Finland, Germany, Hungary, Netherlands, Romania, Russia, Slovakia, Spain, United Kingdom, United States

Participant flow

Recruitment details

First participant enrolled: 30 April 2008, Last participant completed 24 week period: 19 May 2009. 1240 enrolled at 126 centres in 13 countries. Men and women aged ≥18-≤80 years at time of consenting who have inadequate glycaemic control (HbA1c ≥7.5% and ≤10.5%) and are on a stable insulin regimen (≥30 IU of injectable insulin per day for 8 weeks).

Pre-assignment details

For two weeks prior to randomization, participants recorded their daily self monitored plasma glucose and insulin use. At randomization, qualified participants were stratified according to their use of other anti-diabetic (OAD) medication or not. No more than 60% of enrolled participants were to take insulin plus OADs.

Participants by arm

Arm	Count
Placebo Placebo	193
Dapagliflozin 2.5mg Dapagliflozin tablet oral 2.5 mg total daily dose once daily 24 weeks	202
Dapagliflozin 5mg Dapagliflozin tablet oral 5 mg total daily dose once daily 24 weeks	211
Dapagliflozin 10mg Dapagliflozin tablet oral 10 mg total daily dose once daily 24 weeks	194
Total	800

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	6	5	9	6
Overall Study	Death	0	0	1	0
Overall Study	Lost to Follow-up	1	2	1	2
Overall Study	Study criteria,compliance,safety, other	8	5	7	4
Overall Study	Withdrawal by Subject	14	10	8	6

Baseline characteristics

Characteristic	Dapagliflozin 2.5mg	Placebo	Dapagliflozin 5mg	Dapagliflozin 10mg	Total
Age Continuous	59.8 Years STANDARD_DEVIATION 7.64	58.8 Years STANDARD_DEVIATION 8.61	59.3 Years STANDARD_DEVIATION 7.91	59.3 Years STANDARD_DEVIATION 8.75	59.3 Years STANDARD_DEVIATION 8.22
Body Mass Index	32.95 kg/m2 STANDARD_DEVIATION 5.032	33.14 kg/m2 STANDARD_DEVIATION 5.862	32.97 kg/m2 STANDARD_DEVIATION 5.261	33.41 kg/m2 STANDARD_DEVIATION 5.061	33.11 kg/m2 STANDARD_DEVIATION 5.303
Fasting plasma glucose	180.11 mg/dl STANDARD_DEVIATION 59.9	170.62 mg/dl STANDARD_DEVIATION 57.165	185.38 mg/dl STANDARD_DEVIATION 58.712	173.09 mg/dl STANDARD_DEVIATION 54.916	177.58 mg/dl STANDARD_DEVIATION 57.95
HbA1C	8.46 Percent STANDARD_DEVIATION 0.78	8.47 Percent STANDARD_DEVIATION 0.768	8.62 Percent STANDARD_DEVIATION 0.892	8.57 Percent STANDARD_DEVIATION 0.82	8.53 Percent STANDARD_DEVIATION 0.819
Race/Ethnicity, Customized Asian	7 Participants	0 Participants	3 Participants	3 Participants	13 Participants
Race/Ethnicity, Customized Black/African American	3 Participants	6 Participants	5 Participants	5 Participants	19 Participants
Race/Ethnicity, Customized Other	2 Participants	1 Participants	3 Participants	2 Participants	8 Participants
Race/Ethnicity, Customized White	190 Participants	186 Participants	200 Participants	184 Participants	760 Participants
Sex: Female, Male Female	102 Participants	98 Participants	111 Participants	107 Participants	418 Participants
Sex: Female, Male Male	100 Participants	95 Participants	100 Participants	87 Participants	382 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	115 / 197	135 / 202	128 / 212	107 / 196
serious Total, serious adverse events	14 / 197	15 / 202	10 / 212	14 / 196

Outcome results

Primary

Adjusted Mean Change in HbA1c Levels

To assess the efficacy of 2.5 mg, 5 mg and 10 mg dapagliflozin compared to placebo as add-on therapy to insulin in improving glycaemic control in participants with type 2 diabetes who have inadequate glycaemic control on ≥ 30 IU injectable insulin daily for at least 8 weeks prior to enrolment, as determined by the change in HbA1c levels from baseline to Week 24, excluding data after insulin up-titration.

Time frame: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Adjusted Mean Change in HbA1c Levels	-0.30 Percent
Dapagliflozin 2.5mg	Adjusted Mean Change in HbA1c Levels	-0.75 Percent
Dapagliflozin 5mg	Adjusted Mean Change in HbA1c Levels	-0.82 Percent
Dapagliflozin 10mg	Adjusted Mean Change in HbA1c Levels	-0.90 Percent

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided)p-value: <0.000195% CI: [-0.66, -0.38]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided)p-value: <0.000195% CI: [-0.59, -0.31]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided)p-value: <0.000195% CI: [-0.74, -0.45]ANCOVA

Secondary

Adjusted Mean Change in Body Weight

To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing body weight or causing less weight gain as compared to placebo added to insulin treatment after 24 weeks of treatment (LOCF), excluding data after insulin up-titration.

Time frame: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Adjusted Mean Change in Body Weight	0.02 kg
Dapagliflozin 2.5mg	Adjusted Mean Change in Body Weight	-0.98 kg
Dapagliflozin 5mg	Adjusted Mean Change in Body Weight	-0.98 kg
Dapagliflozin 10mg	Adjusted Mean Change in Body Weight	-1.67 kg

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000195% CI: [-1.5, -0.49]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-1.5, -0.5]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-2.19, -1.18]ANCOVA

Secondary

Adjusted Mean Change in Calculated Mean Daily Insulin Dose

To examine whether treatment with dapagliflozin in combination with insulin leads to a lower absolute calculated mean daily insulin dose as compared to placebo added to insulin treatment alone, from baseline to week 24, including data after insulin up-titration.

Time frame: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Adjusted Mean Change in Calculated Mean Daily Insulin Dose	5.08 IU/day
Dapagliflozin 2.5mg	Adjusted Mean Change in Calculated Mean Daily Insulin Dose	-1.80 IU/day
Dapagliflozin 5mg	Adjusted Mean Change in Calculated Mean Daily Insulin Dose	-0.61 IU/day
Dapagliflozin 10mg	Adjusted Mean Change in Calculated Mean Daily Insulin Dose	-1.16 IU/day

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-9.46, -4.28]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-8.25, -3.13]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-8.84, -3.63]ANCOVA

Secondary

Adjusted Mean Change in Fasting Plasma Glucose (FPG)

To examine whether treatment with dapagliflozin in combination with insulin is superior in reducing Fasting Plasma Glucose (FPG) as compared to placebo added to insulin treatment after 24 weeks of treatment, excluding data after insulin up-titration.

Time frame: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Adjusted Mean Change in Fasting Plasma Glucose (FPG)	3.3 mg/dL
Dapagliflozin 2.5mg	Adjusted Mean Change in Fasting Plasma Glucose (FPG)	-12.5 mg/dL
Dapagliflozin 5mg	Adjusted Mean Change in Fasting Plasma Glucose (FPG)	-18.8 mg/dL
Dapagliflozin 10mg	Adjusted Mean Change in Fasting Plasma Glucose (FPG)	-21.7 mg/dL

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000895% CI: [-25, -6.6]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 095% CI: [-31.2, -13.1]ANCOVA

Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-34.3, -15.8]ANCOVA

Secondary

Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction

To examine whether treatment with dapagliflozin in combination with insulin leads to higher percentage of participants with calculated mean daily insulin dose reduction from baseline to week 24 (i.e. reduction \>= 10%) as compared to placebo added to insulin treatment.

Time frame: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Arm	Measure	Value (LEAST_SQUARES_MEAN)
Placebo	Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	11.0 Percentage of participants
Dapagliflozin 2.5mg	Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	18.1 Percentage of participants
Dapagliflozin 5mg	Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	16.8 Percentage of participants
Dapagliflozin 10mg	Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction	19.7 Percentage of participants

Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.042795% CI: [0.2, 14.1]Regression, Logistic

Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.090395% CI: [-0.9, 12.5]Regression, Logistic

Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.016695% CI: [1.6, 15.8]Regression, Logistic

Other Pre-specified

Proportion of Participants With Lack of Glycemic Control

Participants with lack of glycemic control or insulin up-titration for failing to achieve pre-specified glycemic targets

Time frame: Baseline to Week 24

Population: Full Analysis Set

Arm	Measure	Value (NUMBER)
Placebo	Proportion of Participants With Lack of Glycemic Control	54 Participants
Dapagliflozin 2.5mg	Proportion of Participants With Lack of Glycemic Control	22 Participants
Dapagliflozin 5mg	Proportion of Participants With Lack of Glycemic Control	24 Participants
Dapagliflozin 10mg	Proportion of Participants With Lack of Glycemic Control	19 Participants

Efficacy and Safety of Dapagliflozin, Added to Therapy of Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Other

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Adjusted Mean Change in HbA1c Levels

Adjusted Mean Change in Body Weight

Adjusted Mean Change in Calculated Mean Daily Insulin Dose

Adjusted Mean Change in Fasting Plasma Glucose (FPG)

Proportion of Participants With Calculated Mean Daily Insulin Dose Reduction

Proportion of Participants With Lack of Glycemic Control