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

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 (%)

-0.79 -0.40*

-0.89 -0.49*

-0.96 -0.57*

-0.79 -0.32*

-0.96 -0.49*

-1.01 -0.54*

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.

*P <.001

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

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)

-0.92 -1.35*

-1.00 -1.42*

-1.61 -2.04*

-0.96 -1.78*

-1.00* -1.82*

-1.61 -2.43*

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.

*P <.001

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

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)

-1.95 -7.60*

-0.63 -6.28*

-1.18 -6.82*

-0.92 -11.46*

+0.30 -10.24*

-0.70 -11.25*

Wilding JPH, et al. Ann Intern Med. 2012;156:405-415.

*P <.001

% Patients with Mean Daily Dose Reductions ≥ 10% from Baseline

Treatment 24 Weeks 48 Weeks

Placebo + insulin 10.2% 10.5%

Dapagliflozin + insulin DAPA 2.5 mg Difference vs placebo DAPA 5 mg Difference vs placebo DAPA 10 mg Difference vs placebo

+6.3% (P = .064)

+6.3% (P = .060)

+8.9% (P = .013)

+7.6% (P = .030) +7.0% (P = .041)

+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

Dapagliflozin + insulin

DAPA 2.5 mg Mean change from baseline (mmol/L)

DAPA 5 mg Mean change from baseline (mmol/L)

DAPA 10 mg Mean change from baseline (mmol/L)

-0.65*

-1.12*

-1.10*

-0.69*

-0.90*

-0.94*

Wilding JPH, et al. Ann Intern Med. 2012; 156: 405-415.

*P <.001)

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 EffectsDAPA

• 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.