Long-Term Efficacy of Dapagliflozin
in T2DM Patients Receiving
High-Dose Insulin
John P.H. Wilding, DM, FRCP
Efficacy Outcome Measures
• At week 24
– Primary efficacy outcome
 Change in HbA1c
– Secondary efficacy outcomes
 Change in total body weight
 Change in mean daily insulin dose
 Patients with mean daily insulin dose reductions
≥10% from baseline
 Change in fasting plasma glucose
• At week 48
– Are changes seen at 24 weeks maintained?
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Change in HbA1c at 24 and 48 Weeks
Treatment
24 Weeks
48 Weeks
Placebo + insulin
Mean change from baseline (%)
-0.39
-0.47
-0.79
-0.40*
-0.79
-0.32*
-0.89
-0.49*
-0.96
-0.49*
-0.96
-0.57*
-1.01
-0.54*
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (%)
Difference vs placebo (%)
DAPA 5 mg
Mean change from baseline (%)
Difference vs placebo (%)
DAPA 10 mg
Mean change from baseline (%)
Difference vs placebo (%)
*P <.001
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Change in Body Weight at 24 and 48
Weeks
Treatment
24 Weeks
48 Weeks
Placebo + insulin
Mean change from baseline (kg)
+0.43
+0.82
-0.92
-1.35*
-0.96
-1.78*
-1.00
-1.42*
-1.00*
-1.82*
-1.61
-2.04*
-1.61
-2.43*
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (kg)
Difference vs placebo (kg)
DAPA 5 mg
Mean change from baseline (kg)
Difference vs placebo (kg)
DAPA 10 mg
Mean change from baseline (kg)
Difference vs placebo (kg)
*P <.001
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Change in Daily Insulin Dose at 24 and
48 Weeks
Treatment
24 Weeks
48 Weeks
Placebo + insulin
Mean change from baseline (U)
+5.65
+10.54
-1.95
-7.60*
-0.92
-11.46*
-0.63
-6.28*
+0.30
-10.24*
-1.18
-6.82*
-0.70
-11.25*
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (U)
Difference vs placebo (U)
DAPA 5 mg
Mean change from baseline (U)
Difference vs placebo (U)
DAPA 10 mg
Mean change from baseline (U)
Difference vs placebo (U)
*P <.001
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
% Patients with Mean Daily Dose
Reductions ≥ 10% from Baseline
Treatment
Placebo + insulin
Dapagliflozin + insulin
DAPA 2.5 mg
Difference vs placebo
DAPA 5 mg
Difference vs placebo
DAPA 10 mg
Difference vs placebo
24 Weeks
48 Weeks
10.2%
10.5%
+6.3%
(P = .064)
+7.6%
(P = .030)
+6.3%
(P = .060)
+7.0%
(P = .041)
+8.9%
(P = .013)
+8.1%
(P = .024)
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Change in Fasting Plasma Glucose at
24 and 48 Weeks
Treatment
24 Weeks
48 Weeks
DAPA 2.5 mg
Mean change from baseline (mmol/L)
-0.65*
-0.69*
DAPA 5 mg
Mean change from baseline (mmol/L)
-1.12*
-0.90*
DAPA 10 mg
Mean change from baseline (mmol/L)
-1.10*
-0.94*
Dapagliflozin + insulin
*P <.001)
Wilding JPH, et al. Ann Intern Med. 2012; 156: 405-415.
Safety (% Patients)
• Treatment-related adverse events
– Placebo: 20.8%
– DAPA: 21.3% (2.5 mg); 29.2% (5 mg); 29.1% (10 mg)
• Serious adverse events
– Placebo: 13.2%
– DAPA: <13.4%
• ≥1 event of hypoglycemia
– Placebo: 51.8%
– DAPA: 60.4% (2.5 mg); 55.7% (5 mg); 53.6% (10 mg)
• Serious/severe hypoglycemia
– Placebo: 1 hypoglycemic coma
– DAPA: 2 patients in 5 mg group
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Genital/Urinary Tract Infections
• Compared with placebo, a significantly greater
% of patients receiving DAPA had events
suggesting genital infection
• There was no significant difference between
% of placebo and DAPA patients with events
suggesting urinary tract infections
• Most suggestive events were mild to
moderate and responded to routine treatment
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Renal Effects
DAPA
•  Urinary glucose, hematocrit, serum creatinine,
blood urea nitrogen, and cystatin C levels
•  Serum uric acid levels and calculated
creatinine
• Greater absolute changes in the dapagliflozin
groups, compared with placebo
• These changes were not accompanied by
increased rates of renal impairment or failure,
hypotension, dehydration, or hypovolemia
Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.
Conclusions
• Compared with placebo + insulin, DAPA + insulin resulted in significant
reductions from baseline in HbA1c, body weight, mean daily insulin dose,
and fasting plasma glucose, and a significant increase in % patients with
≥10% decrease in daily insulin dose
• In comparison to a decrease in insulin dose in DAPA groups at 24 and 48
weeks, insulin requirement increased in placebo patients
• Benefits seen at 24 weeks were sustained or improved at 48 weeks,
demonstrating that DAPA continues to work as long as the patient’s
kidneys continue to function
• There was no kidney damage associated with DAPA in this study
• Genital/urinary infections were mild to moderate and managed with
routine therapy
• DAPA + insulin is an appropriate choice for T2DM patients who have poor
glycemic control on insulin, particularly those who are obese
Wilding JPH, et al. Ann Intern Med. 2012; 156: 405-415.