Long term efficacy of DAPA in T2DM pts receiving high dose insulin.pdf

Long term efficacy of DAPA in T2DM pts receiving high dose insulin

1. Long-Term Efficacy of Dapagliflozin
in T2DM Patients Receiving
High-Dose Insulin

John P.H. Wilding, DM, FRCP

2. Efficacy Outcome Measures

* At week 24
— Primary efficacy outcome
= Change in HbAlc
— Secondary efficacy outcomes
= Change in total body weight
= Change in mean daily insulin dose

= Patients with mean daily insulin dose reductions
210% 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.

3. Change in HbAlc at 24 and 48 Weeks

mee Weeks | a8 Week

Placebo + insulin

Mean change from baseline (%) -0,39 -0.47
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (%) -0.79 -0.79
Difference vs placebo (%) -0.40* -0.32*
DAPA 5 mg
Mean change from baseline (%) -0.89 pe
Difference vs placebo (%) -0.49* -0.49
DAPA 10 mg 086 ol
Mean change from baseline (%) 057* -0.54*
Difference vs placebo (%) . .
*P <.001

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

4. Change in Body Weight at 24 and 48
Weeks
A Weeks | a Weeks |

Placebo + insulin
Mean change from baseline (kg) +0,43 +0,82
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (kg) -0.92 -0.96
Difference vs placebo (kg) 41.35? -1.78*
DAPA 5 mg
Mean change from baseline (kg) -1.00 -1.00*
Difference vs placebo (kg) -1.42* -1.82*
DAPA 10 mg
Mean change from baseline (kg) “1.61 Be
Difference vs placebo (kg) -2.04* E
*p<.001

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

5. Change in Daily Insulin Dose at 24 and
48 Weeks
A Weeks | a Weeks |

Placebo + insulin
Mean change from baseline (U) +5.65

+10.54
Dapagliflozin + insulin
DAPA 2.5 mg
Mean change from baseline (U) -1.95 -0.92
Difference vs placebo (U) -7.60* -11.46*
DAPA 5 mg
Mean change from baseline (U) -0.63 me
Difference vs placebo (U) -6.28* -10.24
DAPA 10 mg | as aa
Mean change from baseline (U) 682" 11.25"
Difference vs placebo (U) 7 .
*p<.001

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

6. % Patients with Mean Daily Dose
Reductions = 10% from Baseline
| Treatment | 2 Weeks | a Weeks |

Placebo + insulin 10.2% 10.5%
Dapagliflozin + insulin
DAPA 2.5 mg
Difference vs placebo +6.3% +7.6%
(P = .064) (P = .030)
DAPA 5 mg
Difference vs placebo +6.3% +7.0%
(P = .060) (P = .041)
DAPA 10 mg
Difference vs placebo +8.9% +8.1%
(P = .013) (P = .024)

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

7. Change in Fasting Plasma Glucose at
24 and 48 Weeks
| treatment ETT

Dapagliflozin + insulin

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*

*P <.001)

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

8. 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%

21 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.

9. 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.

10. Renal Effects
DAPA

» MA Urinary glucose, hematocrit, serum creatinine,
blood urea nitrogen, and cystatin C levels

+ W 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.

11. 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
210% 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.