FARXIGA in Combination with ONGLYZA Demonstrates Similar Glycemic 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

AstraZeneca AZN presented key data on the use of FARXIGA^® (dapagliflozin) in diverse patient populations with type 2 and type 1 diabetes (T2D, T1D) at the American Diabetes Association (ADA) 78th Scientific Sessions this week in Orlando, FL, June 22-26, 2018.

These studies reinforce the use of dapagliflozin as a treatment option to help improve glycemic control when used with the DPP-4 inhibitor ONGLYZA^® (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.

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.

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.

INDICATION AND LIMITATIONS OF USE FOR FARXIGA (dapagliflozin) tablets 5 mg and 10 mg

FARXIGA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION FOR FARXIGA

Contraindications

• Prior serious hypersensitivity reaction to FARXIGA
• Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or patients on dialysis

Warnings and Precautions

• Hypotension: FARXIGA causes intravascular volume contraction, and symptomatic hypotension can occur. Assess and correct volume status before initiating FARXIGA in patients with impaired renal function, elderly patients, or patients on loop diuretics. Monitor for hypotension
• Ketoacidosis has been reported in patients with type 1 and type 2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue FARXIGA, evaluate and treat promptly. Before initiating FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA may require monitoring and temporary discontinuation in situations known to predispose to ketoacidosis
• Acute Kidney Injury and Impairment in Renal Function: FARXIGA causes intravascular volume contraction and renal impairment, with reports of acute kidney injury requiring hospitalization and dialysis. Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat.
  
  FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function may be more susceptible to these changes. Before initiating FARXIGA, evaluate renal function and monitor periodically. FARXIGA is not recommended in patients with an eGFR persistently between 30 and <60 mL/min/1.73 m²

• Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the risk for urinary tract infections [UTIs] and serious UTIs have been reported with FARXIGA. Evaluate for signs and symptoms of UTIs and treat promptly
• Hypoglycemia: FARXIGA can increase the risk of hypoglycemia when coadministered with insulin and insulin secretagogues. Consider lowering the dose of these agents when coadministered with FARXIGA
• Genital Mycotic Infections: FARXIGA increases the risk of genital mycotic infections, particularly in patients with prior genital mycotic infections. Monitor and treat appropriately
• Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur with FARXIGA. Monitor LDL-C and treat per standard of care
• Bladder cancer: An imbalance in bladder cancers was observed in clinical trials. There were too few cases to determine whether the emergence of these events is related to FARXIGA, and insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. FARXIGA should not be used in patients with active bladder cancer. Use with caution in patients with a history of bladder cancer
• Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo respectively were female genital mycotic infections (8.4% vs. 6.9% vs. 1.5%), nasopharyngitis (6.6% vs. 6.3% vs. 6.2%), and urinary tract infections (5.7% vs. 4.3% vs. 3.7%).

Use in Specific Populations

• Pregnancy: Advise females of potential risk to a fetus especially during the second and third trimesters.
• Lactation: FARXIGA is not recommended when breastfeeding

Please read US Full Prescribing Information and Medication Guide for FARXIGA

INDICATION AND LIMITATIONS OF USE FOR BYDUREON^® (exenatide extended-release) for injectable suspension 2mg

BYDUREON is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise
• Not a substitute for insulin. Should not be used to treat type 1 diabetes mellitus or diabetic ketoacidosis
• Use with prandial insulin has not been studied
• Do not coadminister with other exenatide-containing products
• Not studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis

IMPORTANT SAFETY INFORMATION FOR BYDUREON

WARNING: RISK OF THYROID C-CELL TUMORS

• Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of exenatide extended-release-induced rodent thyroid C-cell tumors has not been determined
• BYDUREON is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with the use of BYDUREON and inform them of symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for detection of MTC in patients treated with BYDUREON

CONTRAINDICATIONS

• Personal or family history of MTC, patients with MEN 2
• Prior serious hypersensitivity reactions to exenatide or product components

WARNINGS AND PRECAUTIONS

• Acute Pancreatitis including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been reported. After initiation, observe patients carefully for symptoms of pancreatitis. If suspected, discontinue promptly and do not restart if confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis
• Hypoglycemia Risk of hypoglycemia is increased when exenatide is coadministered with insulin or insulin secretagogues. Consider lowering the dose of these agents when coadministered with BYDUREON
• Acute Kidney Injury and Impairment of Renal Function Altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure, and acute renal failure, sometimes requiring hemodialysis and kidney transplantation have been reported. Not recommended in patients with severe renal impairment or end-stage renal disease. Use caution in patients with renal transplantation or moderate renal impairment
• Gastrointestinal Disease Because exenatide is commonly associated with gastrointestinal adverse reactions, not recommended in patients with severe gastrointestinal disease (eg, gastroparesis)
• Immunogenicity Patients may develop antibodies to exenatide. Patients with higher titer antibodies may have an attenuated HbA1c response. In clinical trials, attenuated glycemic response was associated with BYDUREON-treated patients. If worsening of or failure to achieve adequate glycemic control occurs, consider alternative antidiabetic therapy
• Hypersensitivity Reports of serious hypersensitivity reactions (eg, anaphylaxis and angioedema). If this occurs, patients should discontinue BYDUREON and promptly seek medical advice
• Injection-Site Reactions Serious reactions (eg, abscess, cellulitis, and necrosis), with or without subcutaneous nodules, have been reported
• Macrovascular Outcomes No clinical studies establishing conclusive evidence of macrovascular risk reduction with exenatide

ADVERSE REACTIONS

Most common (≥5%) and occurring more frequently than comparator in clinical trials: nausea (16.9%), diarrhea (12.7%), headache (8.0%), vomiting (6.8%), constipation (5.9%), injection-site pruritus (5.9%), injection-site nodule (5.3%), and dyspepsia (5.1%).

DRUG INTERACTIONS

• Oral Medications BYDUREON slows gastric emptying and may reduce the rate of absorption of orally administered drugs
• Warfarin Increased international normalized ratio (INR) sometimes associated with bleeding has been reported with concomitant use of exenatide with warfarin. Monitor INR frequently until stable upon initiation of BYDUREON

PREGNANCY

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please read US Full Prescribing Information and Medication Guide for BYDUREON.

INDICATIONS AND LIMITATIONS OF USE FOR ONGLYZA^® (saxagliptin) tablets 5mg

ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATION FOR ONGLYZA

Contraindications

Prior serious hypersensitivity reaction to ONGLYZA

Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA, and in the SAVOR cardiovascular outcomes trial. Observe for pancreatitis. If pancreatitis is suspected, discontinue ONGLYZA.

Heart Failure: In the SAVOR cardiovascular outcomes trial, more patients treated with ONGLYZA were hospitalized for heart failure compared to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and benefits of ONGLYZA in patients who have known risk factors for heart failure. Monitor for signs and symptoms. If heart failure develops, consider discontinuation of ONGLYZA.

Hypoglycemia: When ONGLYZA was used in combination with a sulfonylurea or with insulin, the incidence of confirmed hypoglycemia was increased over that of placebo. Consider lowering the dose of these agents when coadministered with ONGLYZA.

Hypersensitivity Reactions: Serious reactions have been reported in patients treated with ONGLYZA, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA. Use caution in patients with a history of angioedema to another DPP-4 inhibitor.

Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider discontinuing drug if appropriate.

Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If suspected, discontinue ONGLYZA.

Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA.

Most Common Adverse Reactions

Most common adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%).

Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA 5 mg and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD (8.1% vs. 4.3%, respectively).

Drug Interactions

Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with ONGLYZA significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dosage to 2.5 mg once daily.

Use in Specific Populations

In patients with moderate or severe renal impairment, or end-stage renal disease (eGFR <45 mL/min/1.73 m²), recommended dosage is 2.5 mg once daily regardless of meals. ONGLYZA should be administered following hemodialysis. Assess renal function before starting ONGLYZA and periodically thereafter.

Please see US Full Prescribing Information and Medication Guide for ONGLYZA.

NOTES TO EDITORS

About AstraZeneca in Cardiovascular, Renal & Metabolism (CVMD)

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 CVMD 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 commercialization 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 http://www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS.

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