FDA Approves Trijardy XR (empagliflozin/linagliptin/metformin) for Type 2 Diabetes in Adults

In continuation of my update on empagliflozin/linagliptin/metformin 

    

The U.S. Food and Drug Administration (FDA) has approved Trijardy XR (empagliflozin/linagliptin/metformin hydrochloride extended release tablets) to lower blood sugar in adults with type 2 diabetes, along with diet and exercise. Trijardy XR provides three type 2 diabetes medicines in one pill, including Jardiance® (empagliflozin), Tradjenta® (linagliptin) and metformin hydrochloride extended release. Trijardy XR is marketed by Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company (NYSE: LLY).

"Many adults living with type 2 diabetes who are already on a treatment plan including multiple medications still struggle to keep their blood sugar under control, and may require additional agents to reach their A1C targets," said Ralph DeFronzo, M.D., professor and diabetes division chief, UT Health San Antonio. "Adding new medicines to an individual's plan can be challenging for some, which is why new treatment options that can help improve blood sugar without the burden of an increased pill count are important. In addition, type 2 diabetes is a complex disease that often requires the use of multiple antidiabetic medications to improve glycemic control. Having three different diabetes medications in a single tablet is an important advance in diabetes treatment."

In the U.S., both Jardiance and Tradjenta are once-daily tablets used along with diet and exercise to lower blood sugar in adults with type 2 diabetes. Jardiance is also approved to reduce the risk of cardiovascular death in adults with type 2 diabetes who have known cardiovascular disease. Jardiance is not for people with type 1 diabetes or for people with diabetic ketoacidosis (increased ketones in the blood or urine). Tradjenta is not for people with type 1 diabetes or for the treatment of diabetic ketoacidosis. Tradjenta has not been studied in people with a history of pancreatitis and it is unknown if using Tradjenta increases the risk of developing pancreatitis in these people. 

"We are proud to offer Trijardy XR as a new once-daily option combining three well-established medicines, including an extended-release version of metformin, the most commonly prescribed initial treatment for type 2 diabetes, Jardiance, the most prescribed SGLT2 inhibitor, and Tradjenta, the only single-dose DPP-4 inhibitor," said Mohamed Eid, M.D., M.P.H., M.H.A., vice president, Clinical Development & Medical Affairs, Cardio-Metabolism & Respiratory Medicine, Boehringer Ingelheim Pharmaceuticals, Inc. "We believe Trijardy XR has the potential to help adults with type 2 diabetes conveniently manage their treatment, especially those who are taking other medications and working on the necessary lifestyle changes."

Trijardy XR is not recommended for people with type 1 diabetes or diabetic ketoacidosis (increased ketones in the blood or urine). Trijardy XR has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Trijardy XR. The labeling for Trijardy XR contains a warning for lactic acidosis, a rare but serious complication that can occur due to metformin accumulation, and is common to all products containing metformin.

The FDA approval of Trijardy XR is based on two randomized open-label trials that assessed the bioequivalence of empagliflozin, linagliptin and metformin hydrochloride extended release fixed-dose combination tablets and their individual components in healthy adults. The safety profile of Trijardy XR was found to be consistent with its individual components.

"The approval of Trijardy XR reflects our commitment to the diabetes community and to innovation that addresses evolving needs," said Jeff Emmick, M.D. Ph.D., vice president, Product Development, Lilly. "We developed Trijardy XR because many people with type 2 diabetes need help managing this complex condition without adding more pills to their treatment plan. We look forward to making this new option available soon."

Trijardy XR is not for people who have severe kidney problems, end stage renal disease, or are on dialysis, have a serious condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine), or are allergic to Jardiance, Tradjenta, metformin, or any of the ingredients in Trijardy XR. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin, a component of Trijardy XR. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue Trijardy XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using Trijardy XR.

Trijardy XR will be available in four different dosages, including: 5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release; 12.5 mg empagliflozin/2.5 mg linagliptin/1000 mg metformin HCl extended-release; and 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin HCl extended-release.

What is Trijardy XR?

Trijardy XR is a prescription medicine that contains 3 diabetes medicines, empagliflozin (JARDIANCE), linagliptin (TRADJENTA), and metformin hydrochloride. Trijardy XR can be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes, and in adults with type 2 diabetes who have known cardiovascular disease when empagliflozin (JARDIANCE), one of the medicines in Trijardy XR, is needed to reduce the risk of cardiovascular death.

Trijardy XR is not for people with type 1 diabetes, or for people with diabetic ketoacidosis (increased ketones in the blood or urine).

If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take Trijardy XR.

https://www.drugs.com/history/trijardy-xr.html

FDA Approves Rybelsus (semaglutide), the First Oral GLP-1 Analog Treatment for Adults with Type 2 Diabetes

In continuation of my updates on Semaglutide

Novo Nordisk today announced that the U.S. Food and Drug Administration (FDA) has approved Rybelsus (semaglutide) tablets 7 mg or 14 mg for adults with type 2 diabetes that along with diet and exercise may improve blood sugar (glucose).  Rybelsus is the first and only glucagon-like peptide-1 (GLP-1) analog in a pill and a new option for adults with type 2 diabetes who are not achieving their A1C goal with current antidiabetic treatment.

Type 2 diabetes is a global public health issue that impacts more than 28 million people in the U.S. alone.2 Despite existing treatment options, many adults with type 2 diabetes have poorly managed blood sugar that can increase the risk of developing serious diabetes-related complications.

"GLP-1 receptor agonists are effective medications for people with type 2 diabetes but have been underutilized in part because they have, until now, only been available as an injectable treatment," said Vanita R. Aroda, MD, Director of Diabetes Clinical Research, Brigham and Women's Hospital, Boston, MA and a PIONEER clinical trial investigator. "The availability of an oral GLP-1 receptor agonist represents a significant development and primary care providers, specialists and patients alike may now be more receptive to the use of a GLP-1 therapy to help them achieve their blood sugar goals."

The approval of Rybelsus is based on results from 10 PIONEER clinical trials, which enrolled 9,543 participants and included head-to-head studies of Rybelsus vs. sitagliptin, empagliflozin and liraglutide 1.8 mg.4 In the trials, Rybelsus reduced A1C and, as a secondary endpoint, showed reductions in body weight. The most common adverse reactions in the PIONEER trials, reported in ≥5% of patients, were nausea, abdominal pain, diarrhea, decreased appetite, vomiting and constipation. The types and frequency of the adverse reactions were similar across trials.

"People living with type 2 diabetes deserve more innovation, research and support to help them achieve their individual A1C goals," said Todd Hobbs, vice president and U.S. chief medical officer of Novo Nordisk. "With Rybelsus, we have the opportunity to expand use of effective GLP-1 receptor agonist therapy by providing adults with type 2 diabetes an oral medication which was previously only available as an injection to help with managing their blood sugar."

Rybelsus is approved for once-daily use in two therapeutic doses, 7 mg and 14 mg, and will be available in the U.S. beginning in Q4 2019. Initial supply of Rybelsus will come from manufacturing facilities in Denmark; however, future supply for Rybelsus will come from manufacturing facilities in the U.S. In 2015, Novo Nordisk made a strategic investment to build a new manufacturing facility in Clayton, NC to prepare for the future demand for Rybelsus. Additionally, earlier this year Novo Nordisk acquired a tableting and packaging facility in Durham, NC to meet anticipated supply needs for Rybelsus.

Novo Nordisk is working with health insurance providers with a goal of ensuring broad insurance coverage and patient access to the product. A savings card program will be available at the time of launch for eligible commercially-insured patients to keep out of pocket costs down to as little as $10 a month.

The U.S. FDA is still reviewing Novo Nordisk's new drug application (NDA) for Rybelsus seeking an additional indication to reduce the risk of major adverse cardiovascular events (MACE) such as heart attack, stroke, or cardiovascular death in adults with type 2 diabetes and established cardiovascular disease (CVD). A decision is expected in Q1 2020.

Rybelsus is currently under review by several regulatory agencies around the world, including the European Medicines Agency and the Japanese Pharmaceuticals and Medical Devices Agency.

https://en.wikipedia.org/wiki/Semaglutide

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.

FDA Expands Indication For Type 2 Diabetes Treatment Synjardy (Empagliflozin/Metformin Hydrochloride) To Include Treatment-Naïve Adults

In continuation of my update on empagliflozin and metformin

The U.S. Food and Drug Administration has approved an expanded indication for Synjardy (empagliflozin and metformin hydrochloride) tablets to include treatment-naïve adults with type 2 diabetes (T2D). Synjardy, from Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY), is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D when treatment with both empagliflozin and metformin is appropriate.

empagliflozin Metformin

Synjardy is a combination of empagliflozin (Jardiance) and metformin — two medicines with complementary mechanisms of action — to help control blood glucose in adults with T2D. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney. Metformin, a commonly prescribed initial treatment for T2D, lowers glucose production by the liver and its absorption in the intestine.

"Type 2 diabetes is a complex condition, which often requires that people take more than one treatment to manage their blood sugar," said Paul Fonteyne, president and CEO, Boehringer Ingelheim Pharmaceuticals, Inc. "The expanded indication for Synjardy further validates the potential of this combination therapy to help adults with type 2 diabetes who are not at goal, including those already being treated and, now, those at the beginning of their treatment journey."

The Synjardy label was updated to include results from a phase III, double-blind, randomized, active-controlled study that evaluated the efficacy and safety of empagliflozin in combination with metformin as initial therapy compared with the individual components. In the study, at 24 weeks, the combination of empagliflozin 10 mg or 25 mg with metformin 1000 mg or 2000 mg resulted in significant reductions in A1C (a measure of average blood glucose over the past two to three months) compared with the corresponding dose of either component alone.

Synjardy can cause serious side effects, including Lactic Acidosis (a buildup of lactic acid in the blood). Metformin, one of the medicines in Synjardy, can cause lactic acidosis, a rare, but serious condition that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Synjardy is not for the treatment of type 1 diabetes or diabetic ketoacidosis.

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

FDA Approves Glyxambi (empagliflozin and linagliptin) for Type 2 Diabetes

In continuation of my update on empagliflozin

The U.S. Food and Drug Administration (FDA) has approved Glyxambi (empagliflozin/linagliptin) tablets, from Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Eli Lilly and Company (NYSE: LLY), as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2D) when both empagliflozin and linagliptin are appropriate treatments. Glyxambi is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Glyxambi has not been studied in patients with a history of pancreatitis, and it is unknown if using Glyxambi increases the risk of developing pancreatitis in these patients.

Glyxambi is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Glyxambi has not been studied in patients with a history of pancreatitis, and it is unknown if using Glyxambi increases the risk of developing pancreatitis in these patients.

FDA Approves Glyxambi (empagliflozin and linagliptin) for Type 2 Diabetes

Glyxambi for Type 2 diabetes treatment now available by prescription across the U.S.

In continuation of my update on empagliflozin/linagliptin 

                           

Glyxambi® (empagliflozin/linagliptin) tablets are now available by prescription in many leading chain and independent pharmacies across the U.S., including Walgreens and Rite Aid. GLYXAMBI, part of the Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) and Eli Lilly and Company (NYSE: LLY) Diabetes alliance portfolio, is the first and only dual inhibitor combination therapy approved in the U.S. to combine the mechanisms of action of a sodium glucose co-transporter-2 (SGLT2) inhibitor and a dipeptidyl peptidase-4 (DPP-4) inhibitor in a once-daily tablet.

GLYXAMBI is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (T2D) when both empagliflozin and linagliptin are appropriate treatments. GLYXAMBI is a once-daily tablet taken in the morning that combines 10 mg or 25 mg of empagliflozin, an SGLT2 inhibitor, with 5 mg of linagliptin, a DPP-4 inhibitor. GLYXAMBI is not for people with type 1 diabetes or for diabetic ketoacidosis (increased ketones in the blood or urine). If you have had pancreatitis (inflammation of the pancreas) it is not known if you have a higher chance of getting pancreatitis while taking GLYXAMBI.

Glyxambi for Type 2 diabetes treatment now available by prescription across the U.S.

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   ....