MedicalResearch.com Interview with:
Danilo Verge MD MBA
Vice President, CVRM Global Medical Affairs
MedicalResearch.com: What is the background for this study?
Response: Dapagliflozin, an SGLT2 inhibitor (sodium-glucose co-transporter 2), has been shown to improve glycemic control by decreasing glucose reabsorption in the kidneys and inducing urinary glucose clearance. SGLT2 inhibitors have also been shown to be effective in lowering albuminuria and stabilizing eGFR (estimated glomerular filtration rate). The effect of dapagliflozin on UACR (urine albumin-to-creatinine ratio) has been shown to vary among patients.
The objective of this post-hoc analysis, based on the pooled data from 11 randomized, placebo-controlled clinical trials, was to assess baseline characteristics and concurrent changes in cardiovascular (CV) risk markers associated with UACR response to dapagliflozin.
MedicalResearch.com: What are the main findings?
Response: The data shows that reductions in UACR with dapagliflozin are individual to the patient, i.e. cannot be predicted by baseline clinical characteristics. The data also shows that these reductions are associated with changes in blood pressure and eGFR.
MedicalResearch.com: What should readers take away from your report?
Response: Those patients that show reductions in UACR (70% of all the patients) when exposed to dapagliflozin also show decreases in blood pressure and maintenance of eGFR values. However, it was not possible to predict which patients would have this response based only on their baseline clinical characteristics.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: These findings are promising, and additional studies are required to determine whether UACR responders to SGLT2 inhibitors show improved renal-cardio outcomes compared with non-responders.
MedicalResearch.com: Is there anything else you would like to add?
Response: We look forward to presenting the full results of the DECLARE-TIMI 58 trial at the American Health Association annual meeting on November 10, 2018, where the primary cardiovascular safety and efficacy results will be shared, along with details from the secondary renal composite endpoint (>40% decrease in estimated glomerular-filtration rate to<60 mL/min/1.73 m2, new end-stage renal disease, renal or cardiovascular death).
Dapagliflozin is indicated to improve glycemic control in type 2 diabetes. It is not indicated for type 1 diabetes, reduction in serum uric acid or albuminuria or to reduce the risk of CV events, hHF or renal outcomes.
I am an employee of AstraZeneca, which sponsored the study.
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
- 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
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.
|Reduction in albuminuria with dapagliflozin cannot be predicted by baseline clinical characteristics or changes in most other risk markers||Abstract #SA-OR081
Saturday, Oct 27, 2018
Session Title: New Considerations for Renoprotection Clinical Trials [OR1902-2]
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