Farxiga in combination with Onglyza demonstrates similar glycaemic control with additional benefits vs. insulin glargine in patients with type-2 diabetes

Important short-term and long-term data on a potential new use of Farxiga (dapagliflozin) showed significant reductions in HbA1c in patients with type-1 diabetes
 

June 25, 2018
 

AstraZeneca presented key data on Farxiga (dapagliflozin) in diverse patient populations with type-2 and type-1 diabetes (T2D, T1D) at the American Diabetes Association’s (ADA) 78th Scientific Sessions in Orlando, Florida, 22-26 June 2018.

These studies reinforce the use of dapagliflozin as a treatment option to help improve glycaemic control when used with the DPP-4 inhibitor Onglyza (saxagliptin) vs. 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 Farxiga in T1D was also presented.

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 are proud to have developed a highly representative clinical programme 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 safety and efficacy of dapagliflozin in combination with saxagliptin demonstrated non-inferior HbA1c reduction compared to insulin glargine with or without a sulfonylurea and significant reduction in HbA1c vs. glimepiride in patients inadequately controlled on metformin.^1,2 Specifically, results showed:

·       In this 24-week non-inferiority study (N=643), dapagliflozin 10mg and saxagliptin 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 hypoglycaemia (21.3% vs. 38.4%, p<0.001). (Oral 260-OR)¹

·       In a 52-week study (N=443), dapagliflozin 10mg and saxagliptin 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 MmHg vs. 1.0 MmHg,  p=0.007). (Oral 261-OR)²

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.³

Evaluating CV Outcomes in the SGLT-2i Class

New data from the ongoing multinational CVD-REAL study, the first large 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.⁴

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 events (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 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 the SGLT-2i class by 0.87 mL/min/m²/year and dapagliflozin by 1.24 mL/min/m²/year.⁵

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 2018.⁶

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) programme. 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.^7-9  

In both DEPICT-1 and 2, dapagliflozin demonstrated reductions in HbA1c and body weight, and increased time in glycaemic target range vs. placebo in adults with T1D.^7-9 Specifically, results showed:

·       DEPICT-1: At week 52 (N=747), dapagliflozin 5 mg and 10 mg, 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)⁷

·       DEPICT-2: At week 24 (N=813), dapagliflozin 5 mg and 10 mg, respectively, demonstrated a difference vs. placebo in HbA1C of -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 of -3.21% (95% CI: -3.96, -2.45) and -3.74% (95% CI: -4.49, -2.99) (p<0.0001). (Oral 213-OR)⁸

·       Post-hoc pooled analyses from DEPICT-1 and 2: At week 24, dapagliflozin 5 mg and 10 mg, respectively, demonstrated a difference vs. placebo in mean interstitial glucose (-15.48 and -18.90), increased percentage of time in the target glycaemic 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 hypoglycaemia (≤70 mg/dL or ≤54 mg/dL) or nocturnal glucose (≤70 mg/dL). (Late-breaking Poster 125-LB)⁹

Across treatment groups (dapagliflozin 5mg and 10mg compared to placebo), in both DEPICT-1 and 2, hypoglycaemic events, including severe hypoglycaemia were similar. There were numerically more adjudicated definite diabetic ketoacidosis (DKA) events observed in the dapagliflozin group vs. placebo across the studies (4.0% and 3.4% vs. 1.9% for 52 weeks 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.^7-9  

The full list of highlighted AstraZeneca scientific presentations is available in our curtain raiser here, and the comprehensive list can be accessed on the ADA website here. You can also follow us live during ADA 2018 on Twitter and LinkedIn.

NOTES TO EDITORS

About Farxiga (dapagliflozin)

Farxiga is a first-in-class selective inhibitor of human sodium-glucose co-transporter 2 (SGLT-2) indicated as both monotherapy and as part of combination therapy to improve glycaemic control as an adjunct to diet and exercise in adults with T2D. Dapagliflozin is not indicated for T1D or to reduce the risk of CV events, death or hHF.

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVRM)

Cardiovascular, renal and metabolic diseases together form one of AstraZeneca’s main therapy areas and platforms for future growth. By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of CVRM diseases and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. 

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

References 

1. ^{Vilsboll et al. Oral presentation at the American Diabetes Association 78th Scientific Sessions. A1C Reductions of Dapagliflozin Plus Saxagliptin vs. Insulin Glargine in patients With Type-2 Diabetes Inadequately Controlled by Metformin with or without Sulfonylurea (Oral 213-OR, Sunday, June 24, 14:15 - 16:15 EDT).}
2. ^{Frias et al. Oral presentation at the American Diabetes Association 78th Scientific Sessions. Dapagliflozin Plus Saxagliptin Add-On vs. Glimepiride Add-On to Metformin in Patients with Poorly Controlled Type 2 Diabetes (Oral 261-OR, Monday, June 25, 9:45 - 10:00 EDT).}
3. ^{Jabbour et al. Poster presented at the American Diabetes Association 78th Scientific Sessions. DURATION-8 Randomized Controlled Trial 104-Week Results: Once-Weekly Exenatide (ExQW) Plus Once-Daily Dapagliflozin (DAPA) Versus ExQW or DAPA Alone (Late-breaking Poster 104-LB – Monday, June 25, 12:00 - 13:00 EDT).}
4. ^{Kohsaka et al. Poster presented at the American Diabetes Association 78th Scientific Sessions. Lower Risk of CV Events and Death After Initiation of SGLT-2 Inhibitors vs. DPP-4 Inhibitors – Real-world Data from the Multinational CVD-REAL Study (Late-breaking Poster 124-LB, Monday, June 25, 12:00 - 13:00 EDT).}
5. ^{Clegg et al. Poster presented at the American Diabetes Association 78th Scientific Sessions. Impact of SGLT2 Inhibitors (SGLT2i) on Cardiovascular (CV) Risk and Estimated Glomerular Filtration Rate (eGFR) in the EXSCEL Placebo Group (Late-breaking Poster 130-LB – Monday, June 25, 12:00 - 13:00 EDT).}
6. ^{National Institutes of Health. Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT01730534. Accessed May 2018.}
7. ^{Dandona et al. Poster presented at the American Diabetes Association 78th Scientific Sessions. Long-Term Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type-1 Diabetes: The DEPICT-1 Study (Late-breaking Poster 119-LB – Monday, June 25, 12:00 - 13:00 EDT).}
8. ^{Mathieu et al. Oral presentation at the American Diabetes Association 78th Scientific Sessions. Efficacy and Safety of Dapagliflozin in Patients with Inadequately Controlled Type-1 Diabetes: DEPICT-2 Study (Oral 213-OR, Sunday, June 24, 14:15 - 16:15 EDT).}
9. ^{Mathieu et al. Poster presented at the American Diabetes Association 78th Scientific Sessions. Glucose Variables in T1D Studies with Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data from DEPICT-1 and 2 (Late-breaking Poster 125-LB – Monday, June 25, 12:00 - 13:00 EDT).}