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Spotlight: The Many Facets of AstraZeneca’s Farxiga
By Sangeeta Chakraborty, Ph.D.
From a glucose-lowering, anti-diabetic agent to a heart failure medication, the evolution of this SGLT2 inhibitor is quite remarkable. It is now explored as a treatment for hospitalized COVID-19 patients who are at risk of developing serious complications.
In a landmark victory for AstraZeneca, their long-running workhorse of a drug Farxiga received a third approval from the FDA on 6th May 2020 to treat people with heart failure due to reduced ejection fraction (HFrEF). HFrEF, also known as systolic heart failure, is a condition when the left ventricle of the heart doesn’t squeeze forcefully enough to pump the blood out to the body, as a result of which tissues and organs do not get sufficient amounts of oxygenated blood. As per the definition given by American Heart Association (AHA), HHrEF patients have ≤40% ejection volume, which means the ventricle is only pushing out 40% or less of the total ventricular blood with each contraction. Farxiga is now the first drug in the sodium-glucose cotransporter 2 (SGLT2) inhibitor category to be available for the treatment of HFrEF regardless of type 2 diabetes (T2D) status among patients.
Farxiga (dapagliflozin) was first approved in 2014 for the treatment of T2D. Last October, it received its second nod from the FDA to reduce risks of hospitalization for heart failure (HF) among T2D patients. And now, after picking up a third approval, it has been declared suitable to reduce HF risks and associated mortality on a standalone basis regardless of the presence or absence of T2D. It has been quite a remarkable evolution for this drug which has grown from a glucose-lowering agent to medication for heart failure.
Dapagliflozin is a selective SGLT2 inhibitor. SGLT2 is responsible for 90% of the glucose reabsorption in the kidneys, while SGLT1 does only 10% making the former an attractive target for inhibition. Under normal conditions, glucose excretion is not seen in the urine (glucosuria) even though the kidney glomerular mass freely filters glucose molecules. Active transportation by both SGLT1 and SGLT2 reabsorbs all the filtered glucose along with sodium ions through the kidney tubule and returns the glucose to blood via GLUT2 transporters. By selectively inhibiting SGLT2 in the proximal tubule, SGLT2 inhibitors reduce the reabsorption of glucose and increase its urinary excretion. Therapeutic doses of SGLT2 inhibitors usually expel glucose at a rate of 70 to 80 g/day in the urine, thereby reducing high blood glucose levels in patients with T2D.
SGLT2 Inhibitors: From Anti-glycemic Agents to Heart Benefactors
Currently, four SGLT2 inhibitors, dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin are FDA approved for the treatment of T2D either as a monotherapy or as a combination therapy with standard anti-glycemic drug metformin or other diabetic medications along with exercise and diet to reduce blood glucose. By lowering blood glucose, SGLT2 inhibitors bring down plasma HbA1c levels by 0.6-1%.
However, much before their approvals, in 2008, FDA issued draft guidance to the pharmaceutical industry that required evaluation of cardiovascular safety for any new anti-diabetes drug under investigation. The requirement stemmed from prevailing concerns about the increased cardiovascular risk of the anti-diabetes drug group thiazolidinediones (TZD) like rosiglitazone. Since then, every new antidiabetic agent has an associated cardiovascular outcomes trial (CVOT), typically involving T2D patients who are at high cardiovascular risk.
Most notable of all the CVOTs was the EMPA-REG OUTCOME trial for empagliflozin (Jardience by Lilly/Boehringer) which included 7020 T2D patients with high CV risks and demonstrated a 38% reduction in cardiovascular death and a significant 14% reduction in the primary endpoint of major adverse cardiac events (MACE). Another CVOT study, the CANVAS Program (CANagliflozin cardioVascular Assessment Study) for drug canagliflozin, showed similar positive outcomes on CV risks in T2D patients. The risk of MACE was 14% lower with canagliflozin versus placebo.
DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58, the largest cardiovascular outcomes trial for dapagliflozin, included 17,000 T2D patients with established atherosclerotic CV disease or those at risk of developing atherosclerotic CV disease. Although dapagliflozin did not demonstrate any considerable benefits in the primary endpoint of MACE, it did, however, reduce CV associated death or hospitalization for heart failure (HF) by 17%. In effect, all the SGLT2 inhibitors produced consistently positive outcomes in terms of their impact on the cardiovascular system, like slowing the progression of HF, decreasing the rate of hospitalization due to HF, lowering blood pressure and body weight, and lowering of CV events like non-fatal myocardial infarction and stroke.
|Clinical trial||Drug||Primary Outcome (s)||Secondary findings|
|EMPA-REG OUTCOME||Canagliflozin||14% RRR in MACE||32% ↓ all-cause mortality; 38% ↓ CV death|
35% ↓ HF hospitalizationsCANVAS ProgramEmpagliflozin14% RRR in MACE33% ↓ HF hospitalizationsDECLARE-TIMI 58DapagliflozinNo difference in MACE; 14% RRR in HF hospitalization27% ↓ HF hospitalizations
MACE, major adverse cardiovascular event; RRR, relative risk reduction; CV, cardiovascular; HF, heart failure
DAPA-HF Trial: Farxiga’s Promise in Tackling Heart Failure in Non-Diabetics
The Phase 3 Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure (DAPA-HF) trial took cues from earlier trials like the DECLARE-TIMI 58 and CANVAS that demonstrated positive CV outcomes in T2D patients and modified the patient inclusion criterion. The trial enrolled only those patients that presented with chronic heart failure due to reduced ejection fraction (HFrEF) and were receiving standard therapy for CV risks without taking into account their diabetes status. The study clearly showed the superiority of dapagliflozin over placebo in improving survival and reducing HF-related hospitalization among HFrEF patients. Furthermore, the presence or absence of diabetes in these patients had no impact on the HF benefits from the drug.
|Clinical trial||Drug||Primary Outcome (s)||Secondary Outcomes|
|DAPA-HF||Dapagliflozin||18% ↓ CV death||28% ↓ HF hospitalizations|
|30% ↓ worsening HF||17% ↓ all cause mortality|
Possible Cardioprotective Mechanisms of SGLT2 Inhibitors
The cardioprotective effects of SGLT2 inhibitors seen early in the EMPA-REG OUTCOME and CANVAS Program have been suggested to be contributed by glucose-independent mechanisms. There are three hypotheses that could explain the CV benefits of SGLT2 inhibitors.
- Thrifty Substrate Hypothesis: In the presence of SGLT2 inhibitors, the heart preferentially oxidizes ketone bodies like beta-hydroxybutyrate to derive most of the energy rather than glucose or fatty acids. The more energy-efficient fuel improves cardiac and renal work function with antioxidative properties. Multiple processes, such as increased ketone utilization and improved oxygen delivery to heart along with decreases in intravascular blood volume and blood pressure, could work together as cardioprotective mechanisms in the presence of SGLT2 inhibitors.
- NHE Suppression: SGLT2 inhibitors, besides inhibiting SGLT2 transport proteins, also suppress Na+-H+ exchanger 1 (NHE1) in the heart. T2D patients and those with HF risks have higher cardiac NHE1 activity that, in effect, decreases mitochondrial ATP production by reducing the availability of mitochondrial Ca2+ pool. Consequently, there is a higher chance of myocardiocyte injury in such patients reducing their cardiac output even further. But the suppression of cardiac NHE1 by SGLT2 inhibitor increases mitochondrial Ca2+ that stimulates the production of ATP in the heart and improves systolic function.
- Diuresis Model: Excretion of sodium in the urine—natriuresis—is seen with intake of SGLT2 inhibitors as the transporters are responsible for reabsorbing almost 5% of the body’s sodium. Natriuresis and diuresis together lower plasma volume and blood pressure, ultimately reducing stress on the cardiac walls.
From being glucose-lowering agents to the forefront of cardiovascular therapy, SGLT2 inhibitors have carved a solid niche as reliable treatment options for chronic HF or cardiovascular events. In the wake of the recent approval of dapagliflozin, it would not be surprising to see the other SGLT2 inhibitors follow suit. It would be interesting to see the outcomes of current clinical trials (the EMPEROR-Preserved trial with empagliflozin and the DELIVER trial with dapagliflozin) that are evaluating the effects of SGLT2 inhibitors in patients at risk of heart failure with preserved ejection fraction (HFpEF). These studies have the potential to improve the clinical impact of these drugs significantly.
COVID-19 Patients with underlying cardiometabolic diseases appear to be at the highest risk of serious complications. Therefore, AstraZeneca and Saint Luke’s Mid America Heart Institute have initiated a randomized, global, Phase 3, DARE-19 trial to assess the potential of Farxiga in reducing the risk of disease progression, clinical complications, and death due to COVID-19 in patients who also have cardiovascular (CV), metabolic or kidney risk factors.
Editor: Rajaneesh K. Gopinath, Ph.D.
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- https://www.nejm.org/doi/full/10.1056/NEJMoa1812389 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540565/
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