New drug receives FDA approval to reduce risk of cardiovascular death in adults with diabetes

The U.S. Food and Drug Administration today approved a new indication for Jardiance (empagliflozin) to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease.

"Cardiovascular disease is a leading cause of death in adults with type 2 diabetes mellitus," said Jean-Marc Guettier, M.D., C.M., director of the Division of Metabolism and Endocrinology Products in FDA's Center for Drug Evaluation and Research. "Availability of antidiabetes therapies that can help people live longer by reducing the risk of cardiovascular death is an important advance for adults with type 2 diabetes."

According to the Centers for Disease Control and Prevention, death from cardiovascular disease is 70 percent higher in adults with diabetes compared to those without diabetes, and patients with diabetes have a decreased life expectancy driven in large part by premature cardiovascular death.

The FDA's decision is based on a postmarketing study required by the agency when it approved Jardiance in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Jardiance was studied in a postmarket clinical trial of more than 7,000 patients with type 2 diabetes and cardiovascular disease. In the trial, Jardiance was shown to reduce the risk of cardiovascular death compared to a placebo when added to standard of care therapies for diabetes and atherosclerotic cardiovascular disease.

Jardiance can cause dehydration and low blood pressure (hypotension). Jardiance can also cause increased ketones in the blood (ketoacidosis), serious urinary tract infection, acute kidney injury and impairment in renal function, low blood glucose (hypoglycemia) when used with insulin or insulin secretagogues (e.g. sulfonylurea, a medication used to treat type 2 diabetes by increasing the release of insulin in the pancreas), vaginal yeast infections and yeast infections of the penis (genital mycotic infections), and increased cholesterol.

The most common side effects of Jardiance are urinary tract infections and female genital infections.

Jardiance is not intended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Jardiance is contraindicated in patients with a history of serious hypersensitivity reactions to Jardiance, severe renal impairment, end-stage renal disease, or dialysis.

Empagliflozin offers long-term renal protection in Type 2 diabetes

The sodium-glucose cotransporter 2 inhibitor empagliflozin slows renal progression and averts clinical events, shows further analysis of the EMPA-REG OUTCOME trial.

 empagliflozin 

The previously reported primary analysis showed a reduced risk of major cardiovascular events in patients randomly assigned to take empagliflozin 10 or 25 mg daily, compared with placebo, in addition to their existing medication.

As now reported in The New England Journal of Medicine, the researchers found that microvascular events were also significantly less common in the 4132 patients taking either empagliflozin dose than in the 2068 taking placebo, at 14.0% versus 20.5%.

This was driven almost entirely by renal outcomes, report Christoph Wanner (Würzburg University Clinic, Germany) and team.

Incident or worsening nephropathy occurred in 12.7% of the empagliflozin group versus 18.8% of the placebo group, a significant 39% relative reduction. And 11.2% of patients taking empagliflozin versus 16.2% of those taking placebo progressed to macroalbuminuria, equating to a significant 38% risk reduction.

Patients in the empagliflozin group also had a significantly reduced risk of having a doubling of their serum creatinine level and requiring initiation of renal-replacement therapy.

During the first 4 weeks of treatment, patients taking empagliflozin had a reduction in their average estimated glomerular filtration rate (eGFR) of 0.62 and 0.82 mL/min per 1.73 m2 in the 10 and 25 mg dose groups, respectively. After this, however, eGFR in both groups remained relatively stable, with an annual decline of just 0.19 mL/min per 1.73 m2, compared with 1.67 mL/min per 1.73 m2 in the placebo group.

In an editorial that also refers to the just published LEADER trial, Julie Ingelfinger (Massachusetts General Hospital, Boston, USA) and Clifford Rosen (Maine Medical Center Research Institute, Scarborough, USA) agree with the LEADER investigators' view that differences in trial design and participant characteristics do not account for diabetes medications being cardioprotective in some studies but not others.

"We are left with differences that appear encouraging, yet are not a 'home run' with regard to the management of diabetes", they write.

The editorialists hope that, in the future, head-to-head trials of older and newer diabetes therapies "may help to delineate an even more effective treatment plan for the millions of people whose lives are affected by type 2 diabetes."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1515920#t=abstract

Study finds no added benefit of empagliflozin alone or in combination for type 2 diabetes

In continuation of my update on Empagliflozin

Empagliflozin (trade name: Jardiance) has been approved since May 2014 for adults with type 2 diabetes mellitus in whom diet and exercise alone do not provide adequate glycaemic control. In 2014, the German Institute for Quality and Efficiency in Health Care (IQWiG) concluded in its dossier assessment that an added benefit of the drug in comparison with the appropriate comparator therapies was not proven. Partly, the drug manufacturer had presented no relevant data; partly not only the drugs, but also the therapeutic strategies differed; in addition, the indirect comparisons were based on studies unsuitable for the assessment.

The manufacturer now requested a new benefit assessment due to "new scientific findings", and submitted two dossiers: one for empagliflozin alone, and one for empagliflozin in combination with metformin. IQWiG determined in both early benefit assessments that the dossiers still contained no data and analyses relevant or suitable for the research questions. Hence an added benefit of empagliflozin alone or in combination with metformin in comparison with the appropriate comparator therapies is still not proven. The analyses of the large study EMPA-REG-Outcome additionally submitted were unsuitable for an assessment of the added benefit in Germany.

Same studies, same problems

Both the single agent and the combination of empagliflozin with metformin are approved alone or in combination with other blood-glucose lowering drugs including insulin. According to the Federal Joint Committee (G-BA), this resulted in three and four research questions respectively. The manufacturer again presented no relevant data for five of these seven research questions so that an added benefit is not proven. One study of direct comparison as well as several studies for indirect comparisons, all of which had already been cited in the dossier or in the commenting procedure in 2014, were available for the other two research questions.

The assessment of the data from the indirect comparison was incomplete with regard to content, although it had been known to the manufacturer since the first dossier assessment which patient-relevant outcomes were important. In particular, there was no information on specific adverse events for which a disadvantage of empagliflozin versus the comparator therapy was shown. The information provided on one of the indirect comparisons had the same deficiency; furthermore, there were contradictions to the clinical study reports. The second indirect comparison was not evaluable because the studies compared were not sufficiently similar and because therapeutic strategies instead of drugs were compared with one another again.

Hence there was no hint of an added benefit of empagliflozin in comparison with the appropriate comparator therapies for the single agent or for the fixed combination.

Study EMPA-REG-Outcome unsuitable for the assessment of the added benefit

Both dossiers additionally contained a description of the EMPA-REG-Outcome study used by the manufacturer to answer a question posed by the manufacturer itself, i.e. whether empagliflozin (alone or with metformin) in addition to standard treatment offers an added benefit for patients at high cardiovascular risk in comparison with standard treatment alone plus placebo.

The antidiabetic therapy in this study cannot be considered standard treatment, however: The blood-glucose lowering treatment was not escalated appropriately and the upper threshold values mentioned in guidelines were not consistently respected. And even if treatment was escalated, this was mostly done as emergency treatment, but not as part of a planned treatment expansion.

Effects in favour of empagliflozin mainly in Latin America and Asia

Moreover, marked regional differences were notable: Effects in favour of empagliflozin mainly occurred in study centres in Latin America and Asia, whereas in Europe, partly advantages and partly disadvantages of empagliflozin were shown. Finally, the study addressed neither the G-BA's research questions nor the appropriate comparator therapies specified there.

Thomas Kaiser, Head of the IQWiG Drug Assessment Department, commented on this attempt by the manufacturer to prove an added benefit for at least certain patients: "This is a wasted opportunity. It should be welcomed that studies of this size and this duration, which are therefore potentially informative, are conducted. But it was conducted with obvious deficiencies. Experts had pinned high hopes on this study, particularly as, in contrast to other large outcome studies, it appeared to produce positive results at first glance. A thorough analysis of the study and the results in European participants did not confirm this impression, however."

Type 2 diabetes drug significantly reduces hospitalizations, death from heart failure

In continuation of my update on Empagliflozin

For the first time, research shows that a type 2 diabetes drug significantly reduces hospitalizations and death from heart failure.

The findings, from a large clinical trial known as EMPA-REG OUTCOME, were presented by Yale professor of medicine and clinical chief of endocrinology, Dr. Silvio E. Inzucchi, at the 2015 American Heart Association (AHA) Scientific Session in Orlando, Florida on Nov. 9.

Many individuals with type 2 diabetes also have heart failure, a condition in which the heart fails to pump blood effectively. Treatment for heart failure is limited and prior efforts to treat patients with type 2 diabetes drugs showed no benefit for heart failure. But a new class of type 2 diabetes drugs (SGLT2 inhibitors) that reduce blood sugar by increasing its excretion in the urine had not been studied.

In the EMPA-REG trial, patients with type 2 diabetes and risk factors for heart disease were randomized to receive once-daily doses of either the glucose-lowering drug empagliflozin (10 mg or 25 mg doses), or a placebo. The drug or placebo was given in addition to standard care.

At the end of the trial period, investigators found that patients treated with the drug experienced reductions in blood sugar and blood pressure, as well as weight loss, compared to those on placebo. They also found major significant reductions in hospitalizations for heart failure (35%); the combined result for heart failure hospitalization or dying from heart disease (34%); and the combined result for being hospitalized or dying from heart failure (39%).

Type 2 diabetes drug significantly reduces hospitalizations, death from heart failure

Empagliflozin Lowers Blood Pressure | News | Drug Discovery and Development Magazine

We know that, Empagliflozin (see structure) is a SGLT2 inhibitor which is being investigated in clinical trials for the oral treatment of type 2 diabetes by Boehringer Ingelheim and Eli Lilly and Company. It is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 causes blood glucose to be eliminated through the urine via the urethra...

Empagliflozin Lowers Blood Pressure | News | Drug Discovery and Development Magazine   ....