<?xml version="1.0" encoding="UTF-8"?><section ID="ID_b66a347f-aee5-433f-9141-6a7a30a9134e">
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<title>14 CLINICAL STUDIES</title>
<effectiveTime value="20241220"/>
<component>
<section ID="ID_6936111d-e85f-45f1-a8fc-17937c54970e">
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<title>14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus</title>
<text>
<paragraph>The effectiveness of XIGDUO XR has been established in clinical trials of the coadministration of oral dapagliflozin and metformin HCl extended‑release tablets in treatment-naive adult patients inadequately controlled on diet and exercise alone. The coadministration of dapagliflozin and metformin HCl immediate‑release or extended‑release tablets has been studied in adult patients with type 2 diabetes mellitus inadequately controlled on metformin HCl and compared with a sulfonylurea (glipizide) in combination with metformin HCl. Treatment with dapagliflozin plus metformin HCl at all doses produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) compared to placebo in combination with metformin HCl (initial or add-on therapy). HbA1c reductions were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI).</paragraph>
<paragraph>
<content styleCode="underline">Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release</content>
</paragraph>
<paragraph>A total of 1236 treatment-naive adult patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled trials of 24-week duration to evaluate initial therapy with dapagliflozin 5 mg (NCT00643851) or 10 mg (NCT00859898) in combination with metformin extended-release formulation.</paragraph>
<paragraph>In one trial, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: dapagliflozin 10 mg plus metformin HCl extended-release (up to 2,000 mg/day), dapagliflozin 10 mg plus placebo, or metformin HCl extended-release (up to 2,000 mg/day) plus placebo. Metformin HCl extended-release dosage was up-titrated weekly in 500 mg increments, as tolerated, with a median dosage achieved of 2,000 mg.</paragraph>
<paragraph>The combination treatment of dapagliflozin 10 mg plus metformin HCl extended-release provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin HCl extended-release alone (see Table 11 and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin HCl alone and was non-inferior to metformin HCl extended-release monotherapy in lowering HbA1c.</paragraph>
<table width="100%">
<caption>Table 11: Results at Week 24 (LOCF<footnote ID="_Ref22629578">LOCF: last observation (prior to rescue for rescued patients) carried forward.</footnote>) in an Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus</caption>
<col width="48%"/>
<col width="18%"/>
<col width="18%"/>
<col width="17%"/>
<tbody>
<tr>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">10 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl extended‑release</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">10 mg</content>
<br/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Metformin HCl extended‑release</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=211</content>
<footnote ID="_Ref22629668">All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=219</content>
<footnoteRef IDREF="_Ref22629668"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=208</content>
<footnoteRef IDREF="_Ref22629668"/>
</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref22629887">Least squares mean adjusted for baseline value.</footnote>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from dapagliflozin (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.5<footnote ID="_Ref22630017">p-value <0.0001.</footnote>
</paragraph>
<paragraph>(-0.7, -0.3)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from metformin HCl extended‑release (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.5<footnoteRef IDREF="_Ref22630017"/>
</paragraph>
<paragraph>(-0.8, -0.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.0<footnote ID="_Ref22630024">Non-inferior versus metformin HCl extended‑release.</footnote>
</paragraph>
<paragraph>(-0.2, 0.2)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving HbA1c <7% adjusted for baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>46.6%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>31.7%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>35.2%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">FPG (mg/dL)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>189.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>197.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>189.9</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-60.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-46.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-34.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from dapagliflozin (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-13.9<footnoteRef IDREF="_Ref22630017"/>
</paragraph>
<paragraph>(-20.9, -7.0)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from metformin HCl extened‑release (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-25.5<footnoteRef IDREF="_Ref22630017"/>
</paragraph>
<paragraph>(-32.6, -18.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-11.6<footnote ID="_Ref22630565">p-value <0.05.</footnote>
</paragraph>
<paragraph>(-18.6, -4.6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>88.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>88.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>87.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-3.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> Difference from metformin HCl extended‑release (adjusted mean<footnoteRef IDREF="_Ref22629887"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-2.0<footnoteRef IDREF="_Ref22630017"/>
</paragraph>
<paragraph>(-2.6, -1.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-1.4<footnoteRef IDREF="_Ref22630017"/>
</paragraph>
<paragraph>(-2.0, -0.7)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus</content>
</paragraph>
<renderMultiMedia ID="id828096634" referencedObject="ID_59732cbb-49e2-4f81-9427-066694546c2a"/>
<paragraph>In the second trial (NCT00643851), 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: dapagliflozin 5 mg plus metformin HCl extended-release (up to 2,000 mg/day), dapagliflozin 5 mg plus placebo, or metformin HCl extended-release (up to 2,000 mg/day) plus placebo. Metformin HCl extended-release dosage was up-titrated weekly in 500 mg increments, as tolerated, with a median dosage achieved of 2,000 mg.</paragraph>
<paragraph>The combination treatment of dapagliflozin 5 mg plus metformin HCl extended-release provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin HCl extended-release alone (see Table 12).</paragraph>
<table width="100%">
<caption>Table 12: Results at Week 24 (LOCF<footnote ID="_Ref169255448">LOCF: last observation (prior to rescue for rescued patients) carried forward.</footnote>) in an Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin HCl Extended-Release in Adults with Type 2 Diabetes Mellitus</caption>
<col width="47%"/>
<col width="18%"/>
<col width="17%"/>
<col width="18%"/>
<tbody>
<tr>
<td styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">5 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl extended‑release</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">5 mg</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Metformin HCl extended‑release</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=194</content>
<footnote ID="_Ref169255535">All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=203</content>
<footnoteRef IDREF="_Ref169255535"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=201</content>
<footnoteRef IDREF="_Ref169255535"/>
</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>9.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref169255594">Least squares mean adjusted for baseline value.</footnote>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.1</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from dapagliflozin (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.9<footnote ID="_Ref169255642">p-value <0.0001.</footnote>
</paragraph>
<paragraph>(-1.1, -0.6)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from metformin HCl extended-release (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.7<footnoteRef IDREF="_Ref169255642"/>
</paragraph>
<paragraph> (-0.9, -0.5)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving HbA1c <7% adjusted for baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>52.4%<footnote ID="_Ref169255880">p-value <0.05.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>22.5%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>34.6%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">FPG (mg/dL)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>193.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>190.8</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>196.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-61.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-42.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-33.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from dapagliflozin (adjusted mean<footnoteRef IDREF="_Ref169255535"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-19.1<footnoteRef IDREF="_Ref169255642"/>
</paragraph>
<paragraph>(-26.7, -11.4)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from metformin HCl extended‑release (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-27.5<footnoteRef IDREF="_Ref169255642"/>
</paragraph>
<paragraph>(-35.1, -19.8)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>84.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>86.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>85.8</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-1.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> Difference from metformin HCl extended‑release (adjusted mean<footnoteRef IDREF="_Ref169255594"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-1.4<footnoteRef IDREF="_Ref169255642"/>
</paragraph>
<paragraph>(-2.0, -0.7)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="underline">Dapagliflozin Add-On to Metformin HCl Immediate-Release</content>
</paragraph>
<paragraph>A total of 546 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with metformin HCl (NCT00528879). Patients on metformin HCl at a dosage of at least 1,500 mg/day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dosage of metformin HCl.</paragraph>
<paragraph>As add-on treatment to metformin HCl, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 13 and Figure 3). Statistically significant (p<0.05 for both dosages) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were −4.5 mmHg and −5.3 mmHg with dapagliflozin 5 mg and 10 mg plus metformin HCl, respectively.</paragraph>
<table width="100%">
<caption>Table 13: Results of a 24-Week (LOCF<footnote ID="_Ref22632632">LOCF: last observation (prior to rescue for rescued patients) carried forward.</footnote>) Placebo-Controlled Trial of Dapagliflozin in Add-On Combination with Metformin HCl Immediate-Release in Adults with Type 2 Diabetes Mellitus</caption>
<col width="48%"/>
<col width="18%"/>
<col width="18%"/>
<col width="15%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">10 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl immediate-</content>
</paragraph>
<paragraph>
<content styleCode="bold">release</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=135</content>
<footnote ID="_Ref22632670">All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">5 mg</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl immediate-</content>
</paragraph>
<paragraph>
<content styleCode="bold">release</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=137</content>
<footnoteRef IDREF="_Ref22632670"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold"> </content>
</paragraph>
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl immediate-</content>
</paragraph>
<paragraph>
<content styleCode="bold">release </content>
</paragraph>
<paragraph>
<content styleCode="bold">N=137</content>
<footnoteRef IDREF="_Ref22632670"/>
</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>7.9</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref22632694">Least squares mean adjusted for baseline value.</footnote>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.8 </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.3</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref22632694"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.5<footnote ID="_Ref22632750">p-value <0.0001 versus placebo + metformin HCl.</footnote>
</paragraph>
<paragraph>(-0.7, -0.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.4<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(-0.6, -0.2)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Percent of patients achieving HbA1c <7% adjusted for baseline</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>40.6%<footnote ID="_Ref22633148">p-value <0.05 versus placebo + metformin HCl.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>37.5%<footnoteRef IDREF="_Ref22633148"/>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>25.9%</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">FPG (mg/dL)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>156.0 </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>169.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>165.6 </paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline at Week 24 (adjusted mean<footnoteRef IDREF="_Ref22632694"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-23.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-21.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-6.0 </paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref22632694"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-17.5<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(-25.0, -10.0)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-15.5<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(-22.9, -8.1)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline at Week 1 </paragraph>
<paragraph>(adjusted mean<footnoteRef IDREF="_Ref22632694"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-16.5<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(N=115)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-12.0<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(N=121)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.2<br/>(N=126)</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>86.3 </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>84.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>87.7 </paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref22632694"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-2.9 </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-3.0</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.9 </paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref22632694"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-2.0<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(-2.6, -1.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-2.2<footnoteRef IDREF="_Ref22632750"/>
</paragraph>
<paragraph>(-2.8, -1.5)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo-Controlled Trial of Dapagliflozin in Combination with Metformin HCl Immediate-Release in Adults with Type 2 Diabetes Mellitus</content>
</paragraph>
<renderMultiMedia ID="id-897822562" referencedObject="ID_34fb986b-ae27-4f04-9ca4-eac834784394"/>
<paragraph>
<content styleCode="underline">Active Glipizide-Controlled Trial of Dapagliflozin as Add-On to Metformin HCl Immediate-Release in Adults with Type 2 Diabetes Mellitus</content>
</paragraph>
<paragraph>A total of 816 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, non-inferiority trial to evaluate dapagliflozin as add-on therapy to metformin HCl (NCT00660907). Patients on metformin HCl at a dosage of at least 1,500 mg/day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, dosages were kept constant, except for down-titration to prevent hypoglycemia.</paragraph>
<paragraph>At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum trial dosage (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin treatment led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating non-inferiority (see Table 14). Dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin.</paragraph>
<table width="100%">
<caption>Table 14: Results at Week 52 (LOCF<footnote ID="_Ref169256192">LOCF: last observation carried forward.</footnote>) in an Active-Controlled Trial Comparing Dapagliflozin to Glipizide as Add-On to Metformin in Adults with Type 2 Diabetes Mellitus</caption>
<col width="57%"/>
<col width="23%"/>
<col width="19%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Efficacy Parameter</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl</content>
</paragraph>
<paragraph>
<content styleCode="bold">immediate‑release</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=400</content>
<footnote ID="_Ref169256216">Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement.</footnote>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Glipizide</content>
</paragraph>
<paragraph>
<content styleCode="bold">+</content>
</paragraph>
<paragraph>
<content styleCode="bold">Metformin HCl</content>
</paragraph>
<paragraph>
<content styleCode="bold">immediate‑release</content>
</paragraph>
<paragraph>
<content styleCode="bold">N=401</content>
<footnoteRef IDREF="_Ref169256216"/>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>7.7</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>7.7</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref169256250">Least squares mean adjusted for baseline value.</footnote>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.5</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.5</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from glipizide + metformin HCl immediate‑release (adjusted mean<footnoteRef IDREF="_Ref169256250"/>) </paragraph>
<paragraph> (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>0.0<footnote ID="_Ref169256342">Noninferior to glipizide + metformin HCl.</footnote>
</paragraph>
<paragraph>(-0.1, 0.1)</paragraph>
</td>
<td styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Body Weight (kg)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>88.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>87.6</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref169256250"/>) </paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-3.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>1.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph> Difference from glipizide + metformin HCl immediate‑release (adjusted mean<footnoteRef IDREF="_Ref169256250"/>) </paragraph>
<paragraph> (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-4.7<footnote ID="_Ref169256421">p-value <0.0001.</footnote>
</paragraph>
<paragraph>(-5.1, -4.2)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Use in Adults with Type 2 Diabetes Mellitus and Moderate Renal Impairment</content>
</paragraph>
<paragraph>Dapagliflozin was assessed in two placebo-controlled trials of adult patients with type 2 diabetes mellitus and moderate renal impairment.</paragraph>
<paragraph>Patients with type 2 diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 24-week, double-blind, placebo-controlled clinical trial (NCT02413398). Patients were randomized to either dapagliflozin 10 mg or placebo, administered orally once daily. At Week 24, dapagliflozin provided statistically significant reductions in HbA1c compared with placebo (Table 15).</paragraph>
<table width="100%">
<caption>Table 15: Results at Week 24 of Placebo-Controlled Trial for Dapagliflozin in Adults with Type 2 Diabetes Mellitus and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m<sup>2</sup>)</caption>
<col width="50%"/>
<col width="27%"/>
<col width="23%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin 10 mg</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Number of patients:</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=160</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">N=161</content>
</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>8.0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>Change from baseline (adjusted mean<footnote ID="_Ref169256599">Least squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of individuals treated with dapagliflozin and placebo, respectively. Retrieved dropouts, i.e., observed HbA1c at Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.4</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>-0.1</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref169256599"/>) </paragraph>
<paragraph>(95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule " valign="top">
<paragraph>-0.3<footnote ID="_Ref169260308">p-value =0.008 versus placebo.</footnote>
</paragraph>
<paragraph>(-0.5, - 0.1)</paragraph>
</td>
<td styleCode="Rrule Botrule Lrule " valign="top"/>
</tr>
</tbody>
</table>
</text>
<effectiveTime value="20241220"/>
<component>
<observationMedia ID="ID_59732cbb-49e2-4f81-9427-066694546c2a">
<text>Figure 2</text>
<value mediaType="image/jpeg">
<reference value="Figure 2.jpg"/>
</value>
</observationMedia>
</component>
<component>
<observationMedia ID="ID_34fb986b-ae27-4f04-9ca4-eac834784394">
<text>Figure 3: Graph</text>
<value mediaType="image/jpeg">
<reference value="Figure 3.jpg"/>
</value>
</observationMedia>
</component>
</section>
</component>
<component>
<section ID="ID_021ea6ef-d23d-450c-a9f5-9cf8fec41fdc">
<id root="757f403a-536e-4405-ad11-328b1334153b"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.2 Glycemic Control in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus </title>
<text>
<paragraph>
<content styleCode="italics">Glycemic Control Trial of Dapagliflozin in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus</content>
</paragraph>
<paragraph>In a pediatric trial (NCT03199053), patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus (HbA1c ≥6.5% and ≤10.5%) were randomized to dapagliflozin (81 patients) or placebo (76 patients) as add-on to metformin HCl, insulin or a combination of metformin HCl and insulin. In this 26-week, placebo-controlled, double-blind randomized clinical trial with a 26‑week safety extension, patients received 5 mg of dapagliflozin or placebo following a lead-in period. At Week 14, patients with HbA1c values <7% remained on 5 mg while patients with HbA1c values ≥7% were randomized to either continue on 5 mg or up‑titrate to 10 mg.</paragraph>
<paragraph>At baseline, 88% of dapagliflozin-treated patients and 89% of placebo-treated patients were on metformin HCl with or without insulin as background medication. The mean HbA1c at baseline was 8.2% in dapagliflozin-treated patients and 8.0% in placebo-treated patients, and the mean duration of type 2 diabetes mellitus was 2.3 years in dapagliflozin-treated patients and 2.5 years in placebo-treated patients. The mean age was 14.4 years in dapagliflozin-treated patients and 14.7 years in placebo-treated patients, and approximately 61% of dapagliflozin-treated patients and 58% of placebo-treated patients were female. In dapagliflozin-treated patients, approximately 52% were White, 22% were Asian, 9% were Black or African American, and 56% were of Hispanic or Latino ethnicity. In placebo-treated patients, approximately 42% were White, 32% were Asian, 4% were Black or African American, and 45% were of Hispanic or Latino ethnicity. The mean BMI was 29.7 kg/m2 in dapagliflozin-treated patients and 28.5 kg/m2 in placebo-treated patients, and mean BMI Z-score was 1.7 in dapagliflozin-treated patients and 1.5 in placebo-treated patients. The mean eGFR at baseline was 115 mL/min/1.73 m2 in dapagliflozin-treated patients and 113 mL/min/1.73 m<sup>2</sup> in placebo-treated patients.</paragraph>
<paragraph>At Week 26, treatment with dapagliflozin provided statistically significant improvements in HbA1c compared with placebo (Table 16). This effect was consistent across subgroups including race, ethnicity, sex, age group (≥10 to <15 years of age and ≥15 to <18 years of age), background antidiabetic treatment, and baseline BMI.</paragraph>
<paragraph>The treatment benefit with dapagliflozin was consistent in the subgroup of patients with metformin HCl with or without insulin as background therapy [adjusted mean change in HbA1c relative to placebo from baseline to Week 26 was -1.0% (95% CI -1.6, -0.4)].</paragraph>
<table width="100%">
<caption>Table 16: Results at Week 26 in a Placebo-Controlled Trial of Dapagliflozin as Add-On to Metformin HCl and/or Insulin in Pediatric Patients Aged 10 Years and Older with Type 2 Diabetes Mellitus</caption>
<col width="49%"/>
<col width="29%"/>
<col width="22%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Efficacy Parameter</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Dapagliflozin</content>
<br/>
<content styleCode="bold">5 mg and 10 mg</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Placebo</content>
</th>
</tr>
<tr>
<th align="left" styleCode="Rrule Lrule Botrule " valign="top">
<content styleCode="bold">Intent-to-Treat Population (N)</content>
<footnote ID="_Ref169260446">All randomized patients who received at least one dose of double-blind trial medication during the treatment period. Includes data regardless of rescue or premature treatment discontinuation.</footnote>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">81</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">76</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">HbA1c</content>
<footnote ID="_Ref169260516">Multiple imputations using placebo washout approach for missing efficacy endpoint. Imputed for HbA1c (dapagliflozin N=6 (7.4%), placebo N=6 (7.9%)), for FPG (dapagliflozin N=6 (7.4%), placebo N=8 (10.5%)).</footnote>
<content styleCode="bold"> (%)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>8.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>8.0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnote ID="_Ref169260541">Least squares mean adjusted for baseline value, treatment, age, gender and baseline diabetic medication.</footnote>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>-0.6</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.4</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref169260541"/>) <br/> (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>-1.0<footnote ID="_Ref169260592">p-value versus placebo <0.001. p-value is two-sided.</footnote>
</paragraph>
<paragraph>(-1.6, -0.5)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td colspan="3" styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">FPG</content>
<footnoteRef IDREF="_Ref169260516"/>
<content styleCode="bold"> (mg/dL)</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Baseline (mean)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>162.2</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>152.0</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Change from baseline (adjusted mean<footnoteRef IDREF="_Ref169260541"/>)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>-10.3</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>9.2</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph> Difference from placebo (adjusted mean<footnoteRef IDREF="_Ref169260541"/>) (95% CI)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>-19.5<footnote ID="_Ref169260751">p-value versus placebo <0.05. p-value is two-sided.</footnote>
</paragraph>
<paragraph>(-36.4, -2.6)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Percent of Subjects Achieving a HbA1c Level <7%</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>34.6%</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>25.0%</paragraph>
</td>
</tr>
<tr>
<td colspan="3" styleCode="Toprule " valign="top">
<paragraph>CI=confidence interval</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="italics">Glycemic Control Trial of Metformin HCl Immediate-Release in Pediatric Patients Aged 10 to 16 Years with Type 2 Diabetes Mellitus</content>
</paragraph>
<paragraph>A double-blind, placebo-controlled trial was conducted in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), where patients were treated with metformin HCl immediate-release tablets (up to 2,000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks). The results are displayed in Table 17.</paragraph>
<table styleCode="Noautorules" width="100%">
<caption>Table 17: Mean Change in Fasting Plasma Glucose at Week 16 Comparing Metformin HCl vs. Placebo in Pediatric Patients<footnote ID="_Ref169261040">Pediatric patients mean age 13.8 years (range 10-16 years)</footnote> with Type 2 Diabetes Mellitus</caption>
<col width="25%"/>
<col width="25%"/>
<col width="25%"/>
<col width="25%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Metformin HCl</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Placebo</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">p-value</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">FPG</content>
</paragraph>
<paragraph>Baseline</paragraph>
<paragraph>Change at Final Visit</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">(n=37)</content>
</paragraph>
<paragraph>162.4</paragraph>
<paragraph>-42.9</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">(n=36)</content>
</paragraph>
<paragraph>192.3</paragraph>
<paragraph>21.4</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph><0.001</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Mean baseline body weight was 205 lbs and 189 lbs in the metformin HCl immediate-release and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin HCl and placebo arms, respectively.</paragraph>
</text>
<effectiveTime value="20241220"/>
</section>
</component>
<component>
<section ID="ID_404a0b1b-410c-4630-a7e6-8823133aac25">
<id root="fa68b922-0274-4613-ad5e-f530745af402"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.3 Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus </title>
<text>
<paragraph>Dapagliflozin Effect on Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted to determine the effect of dapagliflozin 10 mg relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CV disease or two or more additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.</paragraph>
<paragraph>Of 17160 randomized patients, 6974 (40.6%) had established CV disease and 10186 (59.4%) did not have established CV disease. A total of 8582 patients were randomized to dapagliflozin 10 mg, 8578 to placebo, and patients were followed for a median of 4.2 years.</paragraph>
<paragraph>Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.</paragraph>
<paragraph>Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than 5 years. Mean eGFR was 85.2 mL/min/1.73 m<sup>2</sup>. At baseline, 23.5% of patients had microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m<sup>2</sup>. At baseline, 10% of patients had a history of heart failure.</paragraph>
<paragraph>Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin HCl, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.</paragraph>
<paragraph>Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics.</paragraph>
<paragraph>A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE.</paragraph>
<paragraph>The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with a 95% CI of (0.84, 1.03). The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3.</paragraph>
<paragraph>Dapagliflozin 10 mg was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death [HR 0.83 (95% CI 0.73, 0.95)].</paragraph>
<paragraph>The treatment effect was due to a significant reduction in the risk of hospitalization for heart failure in subjects randomized to dapagliflozin 10 mg [HR 0.73 (95% CI 0.61, 0.88)], with no change in the risk of CV death (Table 18 and Figures 4 and 5).</paragraph>
<table width="100%">
<caption>Table 18: Treatment Effects for the Primary Endpoints* and their Components* in the DECLARE Trial</caption>
<col width="39%"/>
<col width="20%"/>
<col width="13%"/>
<col width="29%"/>
<thead>
<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="middle"/>
<th align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Patients with events n(%)</content>
</th>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
</tr>
<tr>
<th align="left" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Efficacy Variable</content>
<br/>
<content styleCode="bold">(time to first occurrence)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Dapagliflozin 10 mg</content>
<br/>
<content styleCode="bold">N=8582</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Placebo<br/>N=8578</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Hazard Ratio<br/>(95% CI)</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Primary Endpoints</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Composite of Hospitalization for Heart Failure, CV Death<sup>†</sup>
</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>417 (4.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>496 (5.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.83 (0.73, 0.95)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Composite Endpoint of CV Death, MI, Ischemic Stroke</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>756 (8.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>803 (9.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.93 (0.84, 1.03)</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>Components of the composite endpoints<sup>‡</sup>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>Hospitalization for Heart Failure</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>212 (2.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>286 (3.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.73 (0.61, 0.88)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>CV Death</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>245 (2.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>249 (2.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.98 (0.82, 1.17)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>Myocardial Infarction</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>393 (4.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>441 (5.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.89 (0.77, 1.01)</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>Ischemic Stroke</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>235 (2.7)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>231 (2.7)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>1.01 (0.84, 1.21)</paragraph>
</td>
</tr>
<tr>
<td colspan="4" styleCode="Toprule " valign="top">
<list listType="ordered">
<item>
<caption> </caption>N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction, eGFR=estimated glomerular filtration rate, ESRD=End‑stage renal disease</item>
<item>
<caption> </caption>* Full analysis set.</item>
<item>
<caption> </caption>† p-value =0.005 versus placebo.</item>
<item>
<caption> </caption>‡ Total number of events presented for each component of the composite endpoints.</item>
</list>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE Trial</content>
</paragraph>
<renderMultiMedia ID="id-235480729" referencedObject="ID_35e63495-91c9-462a-8967-2da22b86b37b"/>
<paragraph>
<content styleCode="bold">Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Trial</content>
</paragraph>
<renderMultiMedia ID="id560143573" referencedObject="C38B2FDA-4A70-435F-BC0C-57644B1A4A78"/>
</text>
<effectiveTime value="20241220"/>
<component>
<observationMedia ID="ID_35e63495-91c9-462a-8967-2da22b86b37b">
<text>Figure 4</text>
<value mediaType="image/jpeg">
<reference value="Figure 4.jpg"/>
</value>
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</component>
<component>
<observationMedia ID="C38B2FDA-4A70-435F-BC0C-57644B1A4A78">
<text>Figure 5</text>
<value mediaType="image/jpeg">
<reference value="Figure 5.jpg"/>
</value>
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</section>
</component>
<component>
<section ID="ID_de835411-04d8-451b-a775-8eb9905e38f7">
<id root="abe5e525-cbd3-473d-b5e5-78f0745940b0"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.4 Chronic Kidney Disease</title>
<text>
<paragraph>The Trial to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (DAPA-CKD, NCT03036150) was an international, multicenter, randomized, double-blind, placebo-controlled trial in adult patients with chronic kidney disease (CKD) (eGFR between 25 and 75 mL/min/1.73 m<sup>2</sup>) and albuminuria [urine albumin creatinine ratio (UACR) between 200 and 5000 mg/g] who were receiving standard of care background therapy, including a maximally tolerated, labeled daily dosage of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The trial excluded patients with autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis and patients requiring cytotoxic, immunosuppressive, or immunomodulatory therapies in the preceding 6 months.</paragraph>
<paragraph>The primary objective was to determine whether dapagliflozin 10 mg reduces the incidence of the composite endpoint of ≥50% sustained decline in eGFR, progression to end stage kidney disease (ESKD) (defined as sustained eGFR<15 mL/min/1.73 m<sup>2</sup>, initiation of chronic dialysis treatment or renal transplant), CV or renal death.</paragraph>
<paragraph>A total of 4304 patients were randomized equally to dapagliflozin 10 mg or placebo and were followed for a median of 28.5 months. The trial included patients with type 2 diabetes mellitus (n=2906) and patients without diabetes (n=1398). The mean age of the trial population was 62 years and 67% were male. The population was 53% White, 4% Black or African American, and 34% Asian; 25% were of Hispanic or Latino ethnicity. At baseline, mean eGFR was 43 mL/min/1.73 m<sup>2</sup>, 44% of patients had an eGFR 30 mL/min/1.73m<sup>2</sup> to less than 45 mL/min/1.73m<sup>2</sup>, and 15% of patients had an eGFR less than 30 mL/min/1.73m<sup>2</sup>. Median UACR was 950 mg/g. The most common etiologies of CKD were diabetic nephropathy (58%), ischemic/hypertensive nephropathy (16%), and IgA nephropathy (6%). At baseline, 97% of patients were treated with ACEi or ARB. Approximately 44% were taking antiplatelet agents, and 65% were on a statin.</paragraph>
<paragraph>Out of 2906 (68%) patients who had type 2 diabetes mellitus at randomization, 1455 patients received dapagliflozin 10 mg and 1451 received placebo. At baseline of the patients with type 2 diabetes mellitus, 43% were being treated with metformin HCl (631 patients on dapagliflozin 10 mg and 613 on placebo) and 55% were treated with insulin.</paragraph>
<paragraph>The mean age of the type 2 diabetes mellitus trial population was 64 years, 67% were male, 53% White, 5% Black or African American and 32% Asian, 27% were of Hispanic or Latino ethnicity. In these patients, mean eGFR was 44 mL/min/1.73 m<sup>2</sup>, 43% of patients had an eGFR 30 mL/min/1.73 m<sup>2</sup> to below 45 mL/min/1.73 m2, and 14% of patients had an eGFR below 30 mL/min/1.73 m<sup>2</sup>. Median UACR was 1017 mg/g. The most common etiologies of CKD in this group were diabetic nephropathy (86%) and ischemic/hypertensive nephropathy (7%).</paragraph>
<paragraph>Dapagliflozin 10 mg reduced the incidence of the primary composite endpoint of ≥50% sustained decline in eGFR, progression to ESKD, CV or renal death in overall population [HR 0.61 (95% CI 0.51,0.72); p<0.0001]. The dapagliflozin 10 mg and placebo event curves separate by Month 4 and continue to diverge over the trial period. The treatment effect reflected a reduction in ≥50% sustained decline in eGFR, progression to ESKD, and CV death. There were few renal deaths during the trial (Table 19 and Figure 6).</paragraph>
<paragraph>The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the primary composite endpoint in patients with type 2 diabetes mellitus [HR 0.64 (95% CI 0.52, 0.79)] and in patients with type 2 diabetes mellitus and metformin HCl as background therapy [HR 0.74 (95% CI 0.53, 1.03)].</paragraph>
<paragraph>The treatment benefit of dapagliflozin 10 mg was consistent in reducing the incidence of the composite endpoint of CV death or hospitalization for heart failure and all-cause mortality in patients with type 2 diabetes mellitus [HR 0.70 (95% CI 0.53, 0.92) and HR 0.74 (95% CI 0.56, 0.98), respectively] and in patients with type 2 diabetes mellitus and metformin HCl as background therapy [HR 0.59 (95% CI 0.38, 0.91) and HR 0.71 (95% CI 0.46, 1.10)].</paragraph>
<table width="100%">
<caption>Table 19: Treatment Effect for the Primary Composite Endpoint, its Components, and Secondary Composite Endpoints in DAPA CKD Trial</caption>
<col width="38%"/>
<col width="22%"/>
<col width="13%"/>
<col width="17%"/>
<col width="11%"/>
<tbody>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="middle"/>
<td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Patients with events (event rate)</content>
</paragraph>
</td>
<td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Efficacy Variable</content>
</paragraph>
<paragraph>
<content styleCode="bold">(time to first occurrence)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Dapagliflozin 10 mg<br/>N=2152</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Placebo<br/>N=2152</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">Hazard ratio<br/>(95% CI)</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>
<content styleCode="bold">p-value</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Composite of ≥50% sustained eGFR decline, ESKD, CV or renal death</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>197 (4.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>312 (7.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.61<br/>(0.51, 0.72)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph><0.0001</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Components of the primary composite endpoint</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>≥50%<content styleCode="bold"/>Sustained eGFR Decline</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>112 (2.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>201 (4.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.53<br/>(0.42, 0.67)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>ESKD<sup>*</sup>
</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>109 (2.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>161 (3.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.64<br/>(0.50, 0.82)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>CV Death</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>65 (1.4)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>80 (1.7)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.81<br/>(0.58, 1.12)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>Renal Death</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>2 (<0.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>6 (0.1)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">≥50% sustained eGFR decline, ESKD or renal death</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>142 (3.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>243 (5.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.56<br/>(0.45, 0.68)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph><0.0001</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">CV death or Hospitalization for Heart Failure</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>100 (2.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>138 (3.0)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.71<br/>(0.55, 0.92)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.0089</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>Hospitalization for Heart Failure</item>
</list>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>37 (0.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>71 (1.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.51<br/>(0.34, 0.76)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">All-Cause Mortality</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>101 (2.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>146 (3.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.69<br/>(0.53, 0.88)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.0035</paragraph>
</td>
</tr>
<tr>
<td colspan="5" styleCode="Toprule " valign="middle">
<list listType="ordered">
<item>
<caption> </caption>N=Number of patients, CI=Confidence interval, CV=Cardiovascular.</item>
<item>
<caption> </caption>
<content styleCode="bold">
<sup>*</sup>
</content> ESKD is defined as sustained eGFR<15 mL/min/1.73 m<sup>2</sup>, initiation of chronic dialysis treatment, or transplant.</item>
<item>
<caption> </caption>NOTE: Time to first event was analyzed in a Cox proportional hazards model. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.</item>
<item>
<caption> </caption>There were too few events of renal death to compute a reliable hazard ratio.</item>
</list>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 6: Time to First Occurrence of the Primary Composite Endpoint, ≥50% Sustained Decline in eGFR, ESKD, CV or Renal Death (DAPA-CKD Trial)</content>
</paragraph>
<renderMultiMedia ID="id801883835" referencedObject="ID_12927f2d-f2de-49b0-9662-ddbc84e328f9"/>
<paragraph>DAPA-CKD enrolled a population with relatively advanced CKD at high risk of progression. Exploratory analyses of a randomized, double-blind, placebo-controlled trial conducted to determine the effect of dapagliflozin 10 mg on CV outcomes (the DECLARE trial) support the conclusion that dapagliflozin 10 mg is also likely to be effective in patients with less advanced CKD.</paragraph>
</text>
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<text>Figure 6</text>
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</section>
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<section ID="ID_37564521-3346-4f34-8096-b3634358f768">
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<title>14.5 Heart Failure</title>
<text>
<paragraph>The efficacy and safety of dapagliflozin 10 mg were assessed independently in two Phase 3 trials in patients with heart failure.</paragraph>
<paragraph>Dapagliflozin And Prevention of Adverse outcomes in Heart Failure (DAPA-HF, NCT03036124) was an international, multicenter, randomized, double-blind, placebo-controlled trial in adult patients with heart failure [New York Heart Association (NYHA) functional class II-IV] with reduced ejection fraction [left ventricular ejection fraction (LVEF) 40% or less] to determine whether dapagliflozin reduces the risk of cardiovascular death and hospitalization for heart failure. Of 4744 patients, 2373 were randomized to dapagliflozin 10 mg and 2371 to placebo and were followed for a median of 18 months. The trial included patients with type 2 diabetes mellitus (n=2139) and patients without diabetes (n=2605).</paragraph>
<paragraph>Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (DELIVER, NCT03619213) was an international, multicenter, randomized, double-blind, placebo-controlled trial in patients aged ≥40 years with heart failure (NYHA class II-IV) with LVEF >40% and evidence of structural heart disease to determine whether dapagliflozin reduces the risk of cardiovascular death, hospitalization for heart failure or urgent heart failure visits. Of 6263 patients, 3131 were randomized to dapagliflozin 10 mg and 3132 to placebo and were followed for a median of 28 months. The trial included 654 (10%) heart failure patients who were randomized during hospitalization for heart failure or within 30 days of discharge. The trial included patients with type 2 diabetes mellitus (n=2806) and patients without diabetes (n=3457).</paragraph>
<paragraph>In DAPA-HF, at baseline, 94% of patients were treated with ACEi, ARB or angiotensin receptor-neprilysin inhibitor (ARNI, including sacubitril/valsartan 11%), 96% with beta-blocker, 71% with mineralocorticoid receptor antagonist (MRA), 93% with diuretic, and 26% had an implantable device (with defibrillator function). History of type 2 diabetes mellitus was present in 42%, and an additional 3% had type 2 diabetes mellitus based on a HbA1c ≥6.5% at both enrollment and randomization, totaling to 1075 patients in the dapagliflozin group and 1064 in the placebo group. At baseline of the patients with type 2 diabetes mellitus, 48% were treated with metformin HCl (505 patients on dapagliflozin 10 mg and 515 on placebo) and 25% were treated with insulin.</paragraph>
<paragraph>In DAPA-HF, the mean age of the type 2 diabetes mellitus population was 67 years, 78% were male, 70% White, 6% Black or African American and 23% Asian. At baseline, 64% patients were classified as NYHA class II, 35% class III and 1% class IV, median LVEF was 32%. Patients were on standard of care therapy; 93% of type 2 diabetes mellitus patients were treated with ACEi, ARB, or ARNI (11%), 97% with beta-blocker, 71% with MRA, 95% with diuretic and 27% had an implantable device (with defibrillator function). In these patients, mean eGFR was 63 mL/min/1.73 m2.</paragraph>
<paragraph>In DELIVER, at baseline, 77% of patients were treated with ACEi, ARB or ARNI, 83% with beta-blocker, 43% with MRA and 98% with diuretic. History of type 2 diabetes mellitus was present in 45% of the patients. At baseline of the patients with type 2 diabetes mellitus, 58% were treated with metformin HCl (809 patients on dapagliflozin 10 mg and 832 on placebo) and 30% were treated with insulin. </paragraph>
<paragraph>In DELIVER, the mean age of the type 2 diabetes mellitus population was 71 years, 58% were male, 73% White, 3% Black or African American and 18% Asian. At baseline, 74% patients were classified as NYHA class II, 26% class III and 0.4% class IV, 35% of the patients had LVEF ≤49%, 36% had LVEF 50-59% and 29% had LVEF ≥60%. In the type 2 diabetes mellitus population, 80% were treated with ACEi, ARB or ARNI, 84% with beta-blocker, 40% with MRA, and 98% with diuretic. In these patients, mean eGFR was 59 mL/min/1.73 m<sup>2</sup>.</paragraph>
<paragraph>In both trials, dapagliflozin reduced the incidence of the primary composite endpoint of CV death, hospitalization for heart failure or urgent heart failure visit in the overall population (see Table 20). All three components of the primary composite endpoint individually contributed to the treatment effect. In both trials, the dapagliflozin and placebo event curves separated early and continued to diverge over the trial period (see Figure 7).</paragraph>
<table width="99.02%">
<caption>Table 20: Treatment Effect for the Primary Composite Endpoint* and its Components* in the DAPA-HF and DELIVER Trials (Overall Population)</caption>
<col width="16%"/>
<col width="12%"/>
<col width="10%"/>
<col width="10%"/>
<col width="10%"/>
<col width="12%"/>
<col width="10%"/>
<col width="10%"/>
<col width="9%"/>
<thead>
<tr>
<th align="left" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"/>
<th align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">DAPA-HF Trial</content>
</th>
<th align="center" colspan="4" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">DELIVER Trial</content>
</th>
</tr>
<tr>
<th align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Patients with events<br/>(event rate)</content>
</th>
<th align="center" valign="top">
<content styleCode="bold">Hazard ratio<br/>(95% CI)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule " valign="top">
<content styleCode="bold">p-value<sup>†</sup>
</content>
</th>
<th align="center" colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Patients with events<br/>(event rate)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule " valign="top">
<content styleCode="bold">Hazard ratio<br/>(95% CI)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule " valign="top">
<content styleCode="bold">p-value†</content>
</th>
</tr>
<tr>
<th align="left" styleCode="Rrule Lrule Botrule " valign="middle">
<content styleCode="bold">Efficacy Variable</content>
<br/>
<content styleCode="bold">(Time to first occurrence)</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Dapa-gliflozin 10 mg<br/>N=2373</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Placebo<br/>N=2371</content>
</th>
<th align="left" valign="top"/>
<th align="left" styleCode="Rrule Lrule Botrule " valign="top"/>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Dapa-gliflozin 10 mg<br/>N=3131</content>
</th>
<th align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<content styleCode="bold">Placebo<br/>N=3132</content>
</th>
<th align="left" styleCode="Rrule Lrule Botrule " valign="top"/>
<th align="left" styleCode="Rrule Lrule Botrule " valign="top"/>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Composite of Hospitalization for Heart Failure, CV Death</content>
<sup>‡</sup>
<content styleCode="bold"> or Urgent Heart Failure Visit</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>386<br/>(11.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>502<br/>(15.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.74<br/>(0.65, 0.85)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph><0.0001</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>512<br/>(7.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>610<br/>(9.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.82<br/>(0.73, 0.92)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.0008</paragraph>
</td>
</tr>
<tr>
<td colspan="9" styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>
<content styleCode="bold">Components of the composite endpoints</content>
</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>CV Death<sup>‡</sup>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>227<br/>(6.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>273<br/>(7.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.82<br/>(0.69, 0.98)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>231<br/>(3.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>261<br/>(3.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.88<br/>(0.74, 1.05)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>Hospitalization for Heart Failure or Urgent Heart Failure Visit</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>237<br/>(7.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>326<br/>(10.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.70<br/>(0.59, 0.83)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>368<br/>(5.6)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>455<br/>(7.2)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.79<br/>(0.69, 0.91)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>Hospitalization for Heart Failure</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>231<br/>(6.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>318<br/>(9.8)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.70<br/>(0.59, 0.83)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>329<br/>(5.0)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>418<br/>(6.5)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.77<br/>(0.67, 0.89)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="middle">
<paragraph>Urgent Heart Failure Visit</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>10<br/>(0.3)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>23<br/>(0.7)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.43<br/>(0.20, 0.90)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="middle"/>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>60<br/>(0.9)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>78<br/>(1.1)</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle">
<paragraph>0.76<br/>(0.55, 1.07)</paragraph>
</td>
<td styleCode="Rrule Lrule Toprule Botrule " valign="top"/>
</tr>
<tr>
<td colspan="9" styleCode="Toprule " valign="top">
<paragraph>N=Number of patients, CI=Confidence interval, CV=Cardiovascular.</paragraph>
<paragraph>* Full analysis set.</paragraph>
<paragraph>† Two-sided p-values.</paragraph>
<paragraph>‡ In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.</paragraph>
<paragraph>NOTE: Time to first event was analyzed in a Cox proportional hazards model. The number of first events for the single components are the actual number of first events for each component and does not add up to the number of events in the composite endpoint. Event rates are presented as the number of subjects with event per 100 patient years of follow-up.</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>
<content styleCode="bold">Figure 7: Time to the First Occurrence of the Composite of Cardiovascular Death*, Hospitalization for Heart Failure or Urgent Heart Failure Visit</content>
</paragraph>
<paragraph>
<content styleCode="bold">A) DAPA-HF Trial</content>
</paragraph>
<renderMultiMedia ID="id-1058706792" referencedObject="AC3021AC-BB81-4B9B-A5D7-D925F641312A"/>
<paragraph>
<content styleCode="bold">B) DELIVER Trial</content>
</paragraph>
<renderMultiMedia ID="id-1314245864" referencedObject="ID_57aba382-114b-40df-93b3-675730946169"/>
<paragraph>NOTE: An urgent heart failure visit was defined as an urgent, unplanned, assessment by a physician, e.g., in an Emergency Department, and requiring treatment for worsening heart failure (other than just an increase in oral diuretics).</paragraph>
<paragraph>* In DAPA-HF, the CV death component of the primary endpoint included death of undetermined cause. In DELIVER, the CV death component of the primary endpoint excluded death of undetermined cause.</paragraph>
<paragraph>† Patients at risk is the number of patients at risk at the beginning of the period.</paragraph>
<paragraph>HR=Hazard ratio, CI=Confidence interval, CV=Cardiovascular.</paragraph>
<paragraph>The treatment effect of dapagliflozin on the composite endpoint of cardiovascular death, hospitalization for heart failure or urgent heart failure was consistent across the LVEF range as evaluated in DAPA-HF and DELIVER trials (Figure 8).</paragraph>
<paragraph>
<content styleCode="bold">Figure 8: Treatment Effects for Primary Composite Endpoint (Cardiovascular Death and Heart Failure Events) by LVEF (DAPA-HF and DELIVER Trials)</content>
</paragraph>
<renderMultiMedia ID="id-1950150695" referencedObject="ID_5775a12b-aca8-4cfb-8c36-3d5afbe5c433"/>
<paragraph>* 1 patient in DAPA-HF trial had LVEF >40. 4 patients in DELIVER trial had LVEF ≤40.</paragraph>
<paragraph>In DAPA-HF trial, the 5% and 95% percentiles of LVEF were 20 and 40 respectively. In DELIVER trial, the 5% and 95% percentiles of LVEF were 42 and 70, respectively.</paragraph>
<paragraph>In DAPA-HF, the treatment benefit of dapagliflozin 10 mg in reducing the incidence of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus [HR 0.75 (95% CI 0.63, 0.90)], and in patients with type 2 diabetes mellitus and metformin HCl as background therapy [HR 0.67 (95% CI 0.51, 0.88)].</paragraph>
<paragraph>In DELIVER, the treatment benefit of dapagliflozin 10 mg in reducing the incidence of the primary composite endpoint was consistent in patients with type 2 diabetes mellitus [HR 0.83 (95% CI 0.70, 0.97)]. </paragraph>
<paragraph>In DELIVER, the hazard ratio of treatment benefit of dapagliflozin 10 mg in reducing the incidence of the primary composite endpoint in patients with type 2 diabetes mellitus and metformin HCl as background therapy was 0.90 (95% CI 0.72, 1.12).</paragraph>
</text>
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<text>Figure 7 (a)</text>
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<reference value="Figure 7 (a).jpg"/>
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<text>Figure 7 (b)</text>
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<reference value="Figure 7 (b).jpg"/>
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<component>
<observationMedia ID="ID_5775a12b-aca8-4cfb-8c36-3d5afbe5c433">
<text>Figure 8</text>
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<reference value="Figure 8.jpg"/>
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