Data on the use of dapagliflozin in diverse patient populations with type 2 and type 1 diabetes (T2D, T1D) at the American Diabetes Association (ADA) 78th Scientific Sessions in Orlando, Fla. reinforce the use of dapagliflozin as a treatment option to help improve glycemic control when used with the DPP-4 inhibitor saxagliptin versus older treatment options (insulin, sulfonylurea) in patients with T2D. Data investigating the impact of dapagliflozin across patients with a spectrum of cardiovascular (CV) risks were also presented to help further the scientific understanding of the effects of SGLT-2 inhibitors (SGLT-2i) on CV events. In addition, new data investigating dapagliflozin in T1D was also presented. Astra Zeneca markets dapagliflozin and saxagliptin as FARXIGA® and ONGLYZA® , respectively.
Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development, AstraZeneca said: “As demonstrated by the broad data on Farxiga featured at ADA, we are firmly committed to addressing the complex unmet needs of people affected by diabetes, of whom many have interrelated CV risks. Through our completed and ongoing research with Farxiga, we’re proud to have developed a highly representative clinical program that we believe will help change clinical practice for diverse patient populations where there remains a need for earlier and more aggressive treatment approaches with SGLT-2 inhibitors.”
Highlights from the 23 dapagliflozin abstracts presented include:
Dapagliflozin in Combination with Saxagliptin Head-to-Head vs. Insulin or Sulfonylurea in T2D
In T2D, two new phase IIIb studies evaluating the efficacy and safety of dapagliflozin in combination with saxagliptin demonstrated non-inferior HbA1c reduction compared to insulin glargine with or without sulfonylurea and significant reduction in HbA1c vs. glimepiride in patients inadequately controlled on metformin. Specifically, results showed:
• In a 24-week non-inferiority study (N= 643), dapagliflozin 10mg and saxaglipitin 5mg plus metformin in patients with T2D, compared to titrated insulin glargine plus metformin, resulted in similar HbA1c reductions (-1.7% vs. -1.5%, BL~9.0, p=0.118), reduction in body weight (-1.5 kg vs. 2.1 kg, BL~89 kg, p<0.001), reduction in mean 24-hour glucose at week two (-48.5 mg/dL vs. -28.5 mg/dL, p<0.0001) and was associated with a lower prevalence of hypoglycemia (21.3% vs. 38.4%, p<0.001). (Oral 260-OR)
• In a 52-week study (N=443), dapagliflozin 10mg and saxaglipitin 5mg plus metformin in patients with T2D compared to titrated glimepiride plus metformin, resulted in significant reductions in HbA1c (-1.38% vs. -1.14%, BL~8.5, p<0.001), body weight (-3.22 kg vs. 0.89 kg, BL~90 kg, p=0.001) and systolic blood pressure (SBP) (-2.6 mm Hg vs. 1.0, p=0.007). (Oral 261-OR)
Dapagliflozin and saxagliptin are not indicated for weight loss or for treatment of hypertension.
AstraZeneca also presented extension data from the DURATION-8 study over 104 weeks (Late-breaking Poster 104-LB). In this two-year follow-up analysis, the combination of once-daily dapagliflozin 10mg and once-weekly exenatide extended-release 2mg showed greater HbA1c reduction than either drug alone in adult patients with T2D inadequately controlled by metformin alone. The combination and each treatment alone were generally well-tolerated with no unexpected adverse events.
Evaluating CV Outcomes in the SGLT-2i Class
New data from the ongoing multinational CVD-REAL study, the first real-world evidence, study of its kind, were also presented (Late-breaking Poster 124-LB). The late-breaking poster compared the risk of CV events in patients with T2D (N=363,240), 75% of whom did not have established CV disease, starting treatment with dapagliflozin vs. DPP-4is. Initiation of dapagliflozin was associated with lower rates of all-cause death (Hazard Ratio [HR]: 0.61; 95% Confidence Interval [CI]: 0.54, 0.69), hospitalization for heart failure (hHF) (HR: 0.68; 95% CI: 0.60, 0.78), myocardial infarction (HR: 0.90; 95% CI: 0.81, 0.99) and stroke (HR: 0.84; 95% CI: 0.76, 0.93) vs. treatment with DPP-4i. Dapagliflozin is not indicated to reduce the risk of CV events, death or hHF.
AstraZeneca also presented results from a post-hoc analysis of the EXSCEL (Effects of Once-Weekly Exenatide on CV Event Lowering) study, which evaluated CV outcomes for adult patients with T2D at a wide range of CV risk in the placebo arm taking SGLT-2is (Late-breaking Poster 130-LB). This analysis showed an adjusted HR for major adverse cardiac event (MACE), a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke, of 0.79 (95% CI: 0.49,1.28) with the SGLT-2i class and an adjusted HR for of 0.55 (95% CI: 0.26,1.15) with dapagliflozin specifically. Additionally, the adjusted HR for all-cause mortality was 0.51 (95% CI: 0.27,0.95) with the SGLT-2i class and 0.66 (95% CI: 0.25,1.72) with dapagliflozin. Estimated glomerular filtration rate (eGFR) slope increased for both the SGLT-2i class (increased by 0.87 mL/min/m2/year) and dapagliflozin (1.24 mL/min/m2/year). Dapagliflozin is not indicated to improve renal outcomes.
The CV outcomes trial (CVOT) for dapagliflozin, DECLARE (Dapagliflozin Effect on Cardiovascular Events), will evaluate the CV safety and efficacy of dapagliflozin in the largest SGLT-2i CVOT. DECLARE includes a broad range of patients with T2D, including those with multiple CV risk factors or established CV disease. The trial is anticipated to read out in the second half of 2018.
Investigating Dapagliflozin as Add-on to Insulin in T1D to Address an Unmet Need for Oral Therapy
In adults with T1D, AstraZeneca presented short-term and long-term results from the DEPICT (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type-1 Diabetes) program. The new data included results evaluating the efficacy and safety of dapagliflozin as add-on to insulin over 52 weeks (from DEPICT-1) and 24 weeks (from DEPICT-2), as well as a pooled analysis of continuous glucose monitoring (CGM) data from both studies. Dapagliflozin is not indicated for T1D.
In both DEPICT-1 and 2, dapagliflozin demonstrated reductions in HbA1C and body weight, and increased time in glycemic target range vs. placebo in adult patients with T1D. Specifically, results showed:
• DEPICT-1: At week 52 (N=747), dapagliflozin 5mg and 10mg, respectively, demonstrated a difference vs. placebo in HbA1c of -0.33% [95% CI: -0.49, -0.17] and -0.36% (95% CI: -0.53, -0.20) and percent change in body weight of -2.95% (95% CI: -3.83, -2.06) and -4.54% (95% CI: -5.40, -3.66). (Late-breaking Poster 119-LB)
• DEPICT-2: At week 24 (N=813), dapagliflozin 5mg and 10mg respectively, demonstrated a difference vs. placebo in HbA1c (-0.37% [95% CI: -0.49, -0.26] and -0.42% [95% CI: -0.53, -0.30],], BL~8.4, p<0.0001) and percent change in body weight (-3.21% [95% CI: -3.96, -2.45] and -3.74% [95% CI: -4.49, -2.99], p<0.0001). HbA1c (Oral 213-OR)
• Post-hoc pooled analyses from DEPICT-1 and 2: At week 24, dapagliflozin 5mg and 10mg, respectively, demonstrated a difference vs. placebo in reduced mean interstitial glucose (-15.48 and -18.90), increased percentage of time in the target glycemic range, (9.07% equating to more than 2 hours, and 10.67% equating to 2 hours 30 minutes), reduced the Mean Amplitude of Glucose Excursions (MAGE) (-13.36 and -13.94) and reduced postprandial glucose (-8.55 and -12.76), compared to placebo. Dapagliflozin compared to placebo demonstrated no notable difference in hypoglycemia (≤70 mg/dL or ≤54 mg/dL) or nocturnal glucose (≤70 mg/dL). (Late-breaking Poster 125-LB)
Across treatment groups (dapagliflozin 5mg and 10mg compared to placebo), in both DEPICT-1 and 2, hypoglycemic events, including severe hypoglycemia, were similar. There were numerically more adjudicated definite diabetic ketoacidosis (DKA) events observed in the dapagliflozin group vs. placebo across studies (4.0% and 3.4% vs. 1.9% for 52-week in DEPICT-1, and 2.6% and 2.2% vs. 0% for 24 weeks in DEPICT-2). The majority of events were mild or moderate, with the most common identified causes related to missed insulin doses or pump failure.
Loading ...