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A TREATMENT FOR ADULTS WITH TYPE 2 DIABETES MELLITUS, IN ADDITION TO DIET AND EXERCISEDapagliflozin + Metformin vs Glipizide + Metformin

COMPARABLE REDUCTION IN A1C LEVELS VS COMBINATION GLIPIZIDE + METFORMIN

Primary end point: Mean reduction in A1C levels were noninferior to combination therapy
with glipizide + metformin at 52 weeks1,2,a

Dapagliflozin + Metformin vs Glipizide + Metformin clinical trials show comparable a1c reduction vs combination glipizide + metformin. Chart shows down arrows for Dapagliflozin + Metformin vs Glipizide + metformin with Primary end point: Mean reduction in A1C levels were noninferior to combination therapy with glipizide + metformin at 52 weeks. Dapagliflozin + metformin XR showed a mean change from baseline A1C (%) -0.5% and Glipizide + metformin -0.5%.Dapagliflozin + Metformin vs Glipizide + Metformin clinical trials show comparable  a1c reduction vs combination glipizide + metformin. Chart shows down arrows for Dapagliflozin + Metformin vs Glipizide + metformin with Primary end point: Mean reduction in A1C levels were noninferior to combination therapy with glipizide + metformin at 52 weeks. Dapagliflozin + metformin XR showed a mean change from baseline A1C (%) -0.5% and Glipizide + metformin -0.5%.

Values are last observation carried forward and represent adjusted mean change from baseline.

Dapagliflozin + metformin immediate-release were administered as separate tablets.


aPatients on metformin ≥1500 mg per day were randomized following a 2-week placebo lead-in period to glipizide 5 mg or dapagliflozin 2.5 mg and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum study dose (10 mg) vs 73% treated with glipizide (20 mg). Dapagliflozin 2.5 mg is not an FDA-approved dose.

BL=mean baseline.

SIGNIFICANT WEIGHT REDUCTION VS COMBINATION GLIPIZIDE + METFORMIN

Secondary end point: Significant weight reduction at 52 weeks1,2

Significant weight reduction vs combination glipizide + metformin and secondary end point: significant weight reduction at 52 weeks. Downward arrows show mean change in weight (lb) Dapagliflozin + metformin -7.1 lb
vs Glipizide + metformin upward arrows shows +3.1lb with a 10lb difference.Significant weight reduction vs combination glipizide + metformin and secondary end point: significant weight reduction at 52 weeks. Downward arrows show mean change in weight (lb) Dapagliflozin + metformin -7.1 lb vs Glipizide + metformin upward arrows shows +3.1lb with a 10lb difference.

Patients taking dapagliflozin + metformin lost an average of 7.1 lbs while patients taking glipizide + metformin gained an average of 3.1 lbs1,2

 

Values are last observation carried forward and represent adjusted mean change from baseline.


bThe discrepancy between the weight change between treatments and the total weight change results from rounding.

cP<0.0001.

BL=mean baseline.

XIGDUO XR is not indicated for weight loss.

SIGNIFICANTLY GREATER BLOOD PRESSURE REDUCTION

Secondary end point: Significantly greater mean reduction in seated systolic blood pressure
at 52 weeks1-3

Significantly greater blood pressure reductions with a secondary end point: significantly greater mean reduction in seated systolic blood pressure at 52 weeks1. Downward arrows show mean change in seated
systolic blood pressure(mm Hg) Dapagliflozin + metformin -4.3 mm Hg reduction vs Glipizide + metformin upward arrows shows 0.8 mm Hg elevation.Significantly greater blood pressure reductions with a secondary end point: significantly greater mean reduction in seated systolic blood pressure at 52 weeks1. Downward arrows show mean change in seated systolic blood pressure(mm Hg) Dapagliflozin + metformin -4.3 mm Hg reduction vs Glipizide + metformin upward arrows shows 0.8 mm Hg elevation.

Values are last observation carried forward.


dP<0.0001 vs glipizide + metformin.

BL=mean baseline.

Hypotension: Dapagliflozin causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating XIGDUO XR in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension.

XIGDUO XR is not indicated for the treatment of hypertension.
   

FEWER HYPOGLYCEMIC EPISODES VS COMBINATION GLIPIZIDE + METFORMIN

Frequency of minore hypoglycemia was substantially higher with combination therapy
glipizide + metformin1

Fewer hypoglycemic episodes with Dapagliflozin + metformin vs combination glipizide + metformin with a frequency of minor hypoglycemia was substantially higher with combination therapy glipizide + metformin. Minor hypoglycemia using Up arrows show Dapagliflozin + metformin 1.7% and Glipizide + metformin 36%. Major hypoglycemia: up arrows shows Dapagliflozin +metformin 0% and glipizide+ metformin 0.7%Fewer hypoglycemic episodes with Dapagliflozin + metformin vs combination glipizide + metformin with a frequency of minor hypoglycemia was substantially higher with combination therapy glipizide + metformin. Minor hypoglycemia using Up arrows show Dapagliflozin + metformin 1.7% and Glipizide + metformin 36%. Major hypoglycemia: up arrows shows Dapagliflozin +metformin 0% and glipizide+ metformin 0.7%
  • 7 patients taking dapagliflozin + metformin experienced minore hypoglycemia vs 147 patients taking glipizide + metformin over 52 weeks1,2
  • No patients taking dapagliflozin + metformin experienced majorf hypoglycemia over 52 weeks vs 3 patients taking glipizide + metformin1,2

eMinor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement <63 mg/dL, regardless of need for external assistance or an asymptomatic capillary or plasma glucose measurement <63 mg/dL that does not qualify as a major episode.

fMajor episodes of hypoglycemia were defined as symptomatic episodes requiring external (third-party) assistance due to severe impairment in consciousness or behavior with a capillary or plasma glucose value <54 mg/dL and prompt recovery after glucose or glucagon administration.

Use with Medications Known to Cause Hypoglycemia: Consider a lower dose of insulin and insulin secretagogues to reduce risk of hypoglycemia when coadministered with XIGDUO XR.

Hypoglycemia could occur when caloric intake is deficient, strenuous exercise is not compensated by caloric supplementation, or when XIGDUO XR is used with other glucose-lowering agents or ethanol.

STUDY DESIGN1,2

Dapagliflozin + Metformin vs Glipizide + Metformin
Randomized, 52-week, double-blind, parallel-group, active-controlled, multicenter, noninferiority phase 3 study
A1C >6.5% and ≤10.0%
(N=816)
Randomization
Dapagliflozin up-titrated to a maximum dose of 10 mg + metformin (n=400)*
Glipizide up-titrated to a maximum dose of 20 mg + metformin (n=401)*

*Patients received dapagliflozin 2.5 mg or glipizide 5 mg and were up-titrated to optimal glycemic effect (FPG <110 mg/dL) or to the highest dose level (up to dapagliflozin 10 mg and glipizide 20 mg) as tolerated by patients. Metformin dose was ≥1500 mg/day. Dapagliflozin 2.5 mg is not an FDA-approved dose.

Study Objective

Evaluate the efficacy and safety of dapagliflozin vs glipizide as add-on to metformin in adult patients with type 2 diabetes whose A1C is inadequately controlled on metformin monotherapy.

Primary End Point

Change in A1C levels from baseline at Week 52

Select Secondary End Points

  • Change in total body weight from baseline at Week 52
  • Change in seated systolic blood pressure at Week 52

Study Length

52 weeks

Key Inclusion Criteria

Adult patients with type 2 diabetes who had inadequate glycemic control (A1C >6.5% and ≤10.0%) with metformin and had a body mass index (BMI) of ≤45 kg/m2. Patients with systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg were excluded.

Study Dosing

Dapagliflozin was up-titrated to a maximum dose of 10 mg. Glipizide was up-titrated to a maximum dose of 20 mg. Up-titration occurred over 18 weeks, after which doses were kept constant unless down-titration was required to prevent hypoglycemia.