John P.H. Wilding, DM; Vincent Woo, MD; Norman G. Soler, MD, PhD; Andrea Pahor, MD; Jennifer Sugg, MS; Katja Rohwedder, MD; Shamik Parikh, MD; for the Dapagliflozin 006 Study Group
Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, et al. Long-Term Efficacy of Dapagliflozin in Patients With Type 2 Diabetes Mellitus Receiving High Doses of Insulin: A Randomized Trial. Ann Intern Med. 2012;156:405-415. doi: 10.7326/0003-4819-156-6-201203200-00003
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Published: Ann Intern Med. 2012;156(6):405-415.
Dapagliflozin, a selective inhibitor of sodium–glucose cotransporter 2, may improve glycemic control with a lower dose of insulin and attenuate the associated weight gain in patients with inadequate control despite high doses of insulin.
To evaluate the efficacy and safety of adding dapagliflozin therapy in patients whose type 2 diabetes mellitus is inadequately controlled with insulin with or without oral antidiabetic drugs.
A 24-week, randomized, placebo-controlled, multicenter trial followed by a 24-week extension period. An additional 56-week extension period is ongoing. (ClinicalTrials.gov registration number: NCT00673231)
126 centers in Europe and North America from 30 April 2008 to 19 November 2009.
808 patients with inadequately controlled type 2 diabetes mellitus receiving at least 30 U of insulin daily, with or without up to 2 oral antidiabetic drugs.
Patients were randomly assigned in a 1:1:1:1 ratio and allocated with a computer-generated scheme to receive placebo or 2.5, 5, or 10 mg of dapagliflozin, once daily, for 48 weeks.
The primary outcome was change in hemoglobin A1c from baseline to 24 weeks. Secondary outcomes included changes in body weight, insulin dose, and fasting plasma glucose level at 24 weeks and during the 24-week extension period. Adverse events were evaluated throughout both 24-week periods.
800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, −0.40% [95% CI, −0.54% to −0.25%] in the 2.5-mg group, −0.49% [CI, −0.65% to −0.34%] in the 5-mg group, and −0.57% [CI, −0.72% to −0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, −7.60 U [CI, −10.32 to −4.87 U] in the 2.5-mg group, −6.28 U [CI, −8.99 to −3.58 U] in the 5-mg group, and −6.82 U [CI, −9.56 to −4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, −1.35 kg [CI, −1.90 to −0.80 kg] in the 2.5-mg group, −1.42 kg [CI, −1.97 to −0.88 kg] in the 5-mg group, and −2.04 kg [CI, −2.59 to −1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%).
Insulin doses were not titrated to target, and the study was not designed to evaluate long-term safety.
Dapagliflozin improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes in patients with inadequately controlled type 2 diabetes mellitus.
AstraZeneca and Bristol-Myers Squibb.
Persons with type 2 diabetes who receive ongoing insulin therapy may still have inadequate glycemic control, but increasing the insulin dose can result in troubling or dangerous side effects. Dapagliflozin inhibits the renal absorption of glucose and improves glycemic control as monotherapy or when added to metformin in clinical trials.
In this 24-week randomized trial, adding dapagliflozin to insulin therapy for type 2 diabetics with inadequate glycemic control resulted in improved hemoglobin A1c values and weight loss compared with placebo.
Genital infections were more common with dapagliflozin, and the study was not designed to evaluate long-term safety.
Dapagliflozin may be helpful for hyperglycemia in type 2 diabetes that is poorly controlled despite insulin therapy.
Figure 1. Study flow diagram.
DAPA = dapagliflozin; INS = insulin; OAD = oral antidiabetic drug; PLA = placebo.
* This patient received no study medication or postbaseline assessments.
Adjusted mean changes in HbA1c level over time (
top) and at 48 weeks (bottom).
Samples are patients in the full analysis set with nonmissing baseline values and nonmissing values for a given time point. Sample sizes at time 0 are 193, 202, 211, and 193 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively. Treatment group symbols are shifted horizontally to prevent the error bars from overlapping. DAPA = dapagliflozin; HbA1c = hemoglobin A1c; INS = insulin; PLA = placebo.
Figure 3. Adjusted mean changes in total body weight over time (top) and at 48 weeks (bottom).
Samples are patients in the full analysis set with nonmissing baseline values and nonmissing values for a given time point. Sample sizes at time 0 are 193, 202, 211, and 193 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively. Treatment group symbols are shifted horizontally to prevent the error bars from overlapping. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Appendix Figure 1. Adjusted mean changes in daily insulin dose over time (top) and at 48 weeks (bottom).
Samples are patients in the full analysis set with nonmissing baseline values and nonmissing values for a given time point. Sample sizes at time 0 are 191, 200, 209, and 194 for the PLA, 2.5-mg DAPA, 5-mg DAPA, and 10-mg DAPA groups, respectively. Treatment group symbols are shifted horizontally to prevent the error bars from overlapping. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Appendix Figure 2. Probability of insulin up-titration due to not achieving prespecified glycemic targets or of discontinuation due to poor glycemic control over time.
Symbols represent censored observations. “Week” is the actual number of days from the first dose of double-blind study medication divided by 7, not the scheduled visit week. Values for patients at risk are for the beginning of the period. DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Appendix Figure 3. Patients with events suggesting genital infection (top) or urinary tract infection (bottom) at 24 and 48 weeks.
DAPA = dapagliflozin; INS = insulin; PLA = placebo.
Appendix Figure 4.
Change in mean HbA1c level over time calculated by using the placebo group to impute missing data in the safety analysis set and analyzed by treatment group and discontinuation status.
DAPA = dapagliflozin; HbA1c = hemoglobin A1c; INS = insulin; PLA = placebo.
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