Clinical trial finds pioglitazone drug safe and effective for NASH patients

In continuation of my update on Pioglitazone

Researchers have found that an existing diabetes drug can be used to halt progression of another disease that is a leading cause of liver transplants.

A three-year clinical trial led by University of Florida Health researcher Kenneth Cusi, M.D., found that the drug pioglitazone is safe and effective in certain patients who have nonalcoholic steatohepatitis, or NASH, a chronic liver disease caused by a buildup of fat. The findings are published today (June 20) in the journal Annals of Internal Medicine.

NASH is often known as "silent" liver disease and affects 10 to 20 percent of the population and perhaps as many as one-third of all patients with adult-onset diabetes in the United States, according to recent studies. Left unchecked, NASH can cause chronic inflammation that leads to liver cancer or cirrhosis. NASH is now the second-leading cause of liver transplants and the numbers continue to grow each year, said Cusi, chief of the division of endocrinology, diabetes and metabolism in the UF College of Medicine's department of medicine.

Early diagnosis and treatment of NASH is crucial for those who are at greatest risk for the disease, usually obese patients who also have prediabetes or Type 2 diabetes. But until now, Cusi said, there was little urgency to diagnose NASH because there were no available medications.

The research group's single-center clinical trial involving 101 NASH patients with prediabetes or Type 2 diabetes found that pioglitazone reduced fatty liver disease activity in 58 percent of participants. In just more than half the participants -- 51 percent -- the disease was reduced enough that it was no longer considered a threat to the liver.

"The exciting thing is that there is a generic drug that already prevents the onset of Type 2 diabetes and cardiovascular disease in recent studies. Now, it can reduce disease from excess liver fat accumulation and liver inflammation, and halt fibrosis that leads to cirrhosis. This will have a lot of long-term benefits for many people with a medication that will be very affordable and is already being used to treat Type 2 diabetes," Cusi said.

The study also has implications for people with prediabetes and NASH because fatty liver disease is a risk factor for Type 2 diabetes even in those who aren't obese, researchers said.

Federal regulators approved Actos (pioglitazone) in 2000 and a generic version of the drug in 2012 to improve blood glucose control in adults with Type 2 diabetes. Still, pioglitazone's use against liver disease will require a larger, multicenter clinical trial that could take seven years or more in addition to U.S. Food and Drug Administration approval. A multicenter trial would allow researchers to learn more about the drug's long-term benefits for liver issues and determine why some participants respond better than others to the medication, Cusi said.

Researchers aren't entirely certain about how pioglitazone works against liver disease. Patients with NASH are insulin-resistant, meaning their body does not respond normally to their own insulin. This defect promotes fat accumulation and inflammation in the liver. The researchers believe the medication makes molecular improvements in the liver and other tissues such as fat. That helps the body's response to insulin, making it insulin-sensitive again and restoring normal metabolism.

Despite the recent trial's relatively small size, Cusi noted that it's the largest single-center study and the first long-term study examining the drug as treatment for people who have NASH along with prediabetes or Type 2 diabetes. It is also the longest NASH-related study with any drug and had the greatest treatment effect on NASH compared with other approaches, he said.

Pioglitazone, may halt the growth of cysts in Polycystic Kidney Disease....

Recently, researchers from the schools of Science and Medicine at Indiana University-Purdue University Indianapolis and colleagues from the Mayo Clinic reported that drug Pioglitazone, (see structure Enantiomers) commonly used to treat diabetes may also retard the growth of fluid-filled cysts of the most common genetic disorder, polycystic kidney disease.

Using a rat model that has the same genetic mutation as a form of human PKD, the two research groups independently tested a pioglitazone treatment regimen and found that it slowed down both kidney and liver cyst growth by inhibiting a chloride channel in the cells of these organs. Authors claim that the, though the idea of using a chloride channel inhibitor to treat PKD is not new, but usage of an insulin sensitizing agent like piogltiazone inhibits chloride channels is new. The finding that pioglitazone, which has already been approved by the Food and Drug Administration for diabetes, can halt cyst progression and may be an effective and well-tolerated treatment for this chronic disease, is exciting. Confirmation of these results in other animal models of PKD would be a useful next step.....

Ref : http://medicine.iupui.edu/GAST/NEJM%20Article.pdf

Takeda Receives FDA Approval for Oseni (alogliptin and pioglitazone) for Type 2 Diabetes

In continuation of y update on pioglitazone

Takeda Pharmaceutical Company Limited (Takeda) and its wholly-owned subsidiary, Takeda Pharmaceuticals U.S.A., Inc. today announced that the United States (U.S.) Food and Drug Administration (FDA) has approved Oseni (alogliptin and pioglitazone) for the treatment of type 2 diabetes in adults as adjuncts to diet and exercise.

Takeda Receives FDA Approval for Oseni (alogliptin and pioglitazone) for Type 2 Diabetes

Diabetes drug shows promise in treatment of neurodegenerative disease

In continuation of my update on Pioglitazone

We know that, Pioglitazone is a prescription drug of the class thiazolidinedione (TZD) with hypoglycemic (antihyperglycemic, antidiabetic) action to treat diabetes. It is used to improve glucose control in adults over the age of 18 with type 2 diabetes. Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe, Glizone and Pioz in India by Zydus Cadila and USV Limited, respectively and Zactos in Mexico by Takeda Pharmaceuticals....

Now Researchers in Spain have found that a drug used to control Type II diabetes can help repair the spinal cords of mice suffering from the inherited disease adrenoleukodystrophy which, untreated, leads eventually to a paralysis, a vegetative state and death. They believe that their findings may be relevant to other neurodegenerative diseases. A Phase II trial will be starting shortly. ...

More : http://brain.oxfordjournals.org/content/136/3/891.abstract?sid=08e53c88-b470-4a40-844f-4a1e57b570d9

Diabetes drug shows promise in treatment of neurodegenerative disease

Encouraging results from first phase III clinical trials of Balaglitazone (an anti-diabetic drug)......

Balaglitazone (CAS-199113-98-9),5-[[4-[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy]phenyl-methyl]thiazolidine-2,4-dione, (see structure) is a novel partial agonist of PPAR-gamma, which elicits only 52% of the PPAR-gamma activation observed with both pio- and rosiglitazone.

            

Pre-clinical studies have indicated that besides robust glucose lowering ability, balaglitazone results in lower body fluid accumulation, lower fat accumulation, less heart enlargement and no reduction of bone formation, indicating that Balaglitazone may be able to displace the balance between desired and side effects, and thus show a better safety profile than full agonists of PPAR-gamma.

 Now Reddy's Lab, has come up with interesting results from its  Phase III clinical trial programme.The study explored the impact of adding placebo, Balaglitazone 10mg, Balaglitazone 20mg or Pioglitazone 45mg to a background treatment regimen of stable insulin therapy for a period of 26 weeks. The primary endpoint was HbA1c reduction, while several secondary endpoints including fasting plasma glucose, oedema, weight gain, and body composition were considered.

In all, 409 patients were randomized in roughly equal proportions across the four arms of the study. All three active arms (Balaglitazone 10mg, 20mg and Pioglitazone 45mg) showed similar levels of efficacy with respect to both HbA1c and fasting plasma glucose.

All three active arms showed good tolerability and adverse event profile, with Balaglitazone 10mg demonstrating less water retention, less fat accumulation, lower weight/BMI gain and less bone loss when compared to the Pioglitazone arm.

Encourged by these results both companies (Dr. Reddy's & Rheoscience) are planning for detailed studies required for registration of  Balaglitazone.

Type 2 diabetes is a major cause of morbidity and mortality in the industrialized world, with cardiovascular disease as the leading cause of death, accounting for almost 50% of all T2D deaths. Furthermore, the number of T2D patients is increasing rapidly, and the number of patients is expected to reach between 300 and 380 million by 2025, thereby placing an enormous economical burden on global healthcare. Hope new drugs will take care of this problem.



Ref : http://www.drreddys.com/media/popups/jan4_2010.html

Investigational diabetes drug appears to improve insulin sensitivity without side effects

Drugs for type 2 diabetes can contribute to weight gain, bone fractures and cardiovascular problems, but in mice, an investigational drug appears to improve insulin sensitivity without those troublesome side effects, researchers at Washington University School of Medicine in St. Louis have shown.

"Current diabetes medications activate a receptor that improves insulin sensitivity, but unfortunately also contributes to side effects that make some people discontinue the medication, contributing to other health problems," says principal investigator Brian N. Finck, PhD. "So even though these drugs are effective, we'd really like to find new insulin-sensitizing therapies that would avoid activating the same receptor."

Finck, a research assistant professor of medicine in the Division of Geriatrics and Nutritional Science, worked with colleagues at the University of Michigan and at the drug discovery company Metabolic Solutions Development Co., LLC. The scientists studied one of the company's investigational drugs, MSD-0602, focusing on its effects in obese mice.

The drug improved blood glucose levels and insulin tolerance in the mice, as did the two diabetes drugs that already are on the market: rosiglitazone (Avandia) and pioglitazone (Actos). All three medications appeared to be about equally effective, but MSD-0602 didn't bind to and activate a receptor in cells called PPARγ. Rather, the investigational drug clings to the mitochondria, part of the cell that produces energy.

"The drug altered the cell's ability to generate energy," Finck says. "And it also seems to have an anti-inflammatory role in the cell. We also found that the drug improved insulin sensitivity in many different kinds of cells including muscle, fat and liver cells."

 Next, he and his colleagues will attempt to identify proteins that bind to the mitochondrial membrane. Future therapies then could be developed specifically to bind to those proteins while avoiding activation of the PPARγ pathway.

Investigational diabetes drug appears to improve insulin sensitivity without side effects: Drugs for type 2 diabetes can contribute to weight gain, bone fractures and cardiovascular problems, but in mice, an investigational drug appears to improve insulin sensitivity without those troublesome side effects, researchers at Washington University School of Medicine in St. Louis have shown.

Ref : http://www.jbc.org/content/early/2012/05/23/jbc.M112.363960.full.pdf

We know that, Linagliptin (BI-1356, trade name Tradjenta) is a DPP-4 inhibitor developed by Boehringer Ingelheim for treatment of type II diabetes. Linagliptin (once-daily) was approved by the US FDA on 2 May 2011 for treatment of type II diabetes. It is being marketed by Boehringer Ingelheim and Lilly.

Now the companies have announced results of a 102 week Phase III study for linagliptin (trade name Trajenta® in Europe), which show meaningful and durable reductions in blood glucose for adults with type 2 diabetes (T2D). In the two-year study presented today at the 47^th Annual Meeting of the European Association for the Study of Diabetes (EASD), the DPP-4 inhibitor linagliptin showed a favourable safety profile and lowered HbA1c levels by 0.8% over the long term in those patients treated with linagliptin for the full study period. 

Researchers conclude that, these results show that the efficacy achieved by linagliptin is reliable and meaningful in a clinical setting, but also that it is durable over the long term. This is especially important in chronic conditions such as type 2 diabetes.

The data from these patients demonstrate the efficacy and tolerability of linagliptin as mono-, dual- (plus metformin or initial combination with pioglitazone) or triple (plus metformin and sulphonylurea) oral therapy over a period of 102 weeks. Reductions in HbA1c of 0.8% after 24 weeks of blinded treatment were seen to be durable over the additional 78 weeks. Overall, the rate of hypoglycaemic events was low and body weight remained unchanged.

More..

Lilly, Boehringer Ingelheim announce results from linagliptin Phase III trial on T2D

 In continuation of my update on Linagliptin

Results of the one Phase III study presented (Poster No. 999-P) showed that linagliptin was effective as an add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone in reducing blood glucose levels in adult patients with T2D, when compared to placebo as an add-on to these background therapies. Linagliptin demonstrated a placebo-adjusted reduction in HbA1c of 0.65% (p<0.0001) from a baseline HbA1c of 8.3% at 24 weeks without weight gain or additional risk of hypoglycaemia.  HbA1c is measured in people with diabetes to provide an index of blood glucose control for the previous two to three months. 

A post-hoc analysis from a second Phase III trial (Poster No. 1044-P) found that in hyperglycaemic patients on a background of metformin randomised to add linagliptin or glimepiride, a greater proportion of patients taking linagliptin achieved target HbA1c <7% without weight gain and/or hypoglycaemia than those taking glimepiride after 104 weeks (linagliptin 54% versus glimepiride 23%) while comparably improving blood glucose levels.

Ref : http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2012/09_june_2012_linagliptin1.html