Oral Meds on the Horizon
The last few years were good ones when you consider the new injectable options for people with type 2 and type 1 diabetes. The introduction of Byetta® and Symlin® alone have turned the treatment of type 2 on its ear, and the fast- and long-acting insulins Apidra® and Levemir® arrived on the scene to broaden the insulin landscape.
Not much excitement, however, has been generated in the area of new oral medications for people with type 2 diabetes. Januvia® made its debut last year, and more DPP-4 inhibitors like it decorate the horizon. Beyond that, it might be a few years before we see anything groundbreaking.
Here are just a few of the oral medications for diabetes that are in the works:
Galvus®, also known as vildagliptin, is one-such investigative DPP-4 oral medication for the treatment of type 2 diabetes. Galvus®, which is being developed by Novartis, works by increasing insulin production at the most crucial time—right after you eat. In addition, it also reduces the amount of blood glucose your body makes from the liver after you have eaten.
In September 2007, Galvus® received approval in Europe for use in combination with metformin, TZDs, or a sulfonylurea. Galvus®, however, has encountered roadblocks from the U.S. Food and Drug Administration due in part to issues related to liver toxicity at higher doses. In November 2006, the FDA asked for additional safety data.
Kelly Close, a dLife columnist and editor-in-chief of diaTribe—a newsletter on research and new products for patients with diabetes—says that, at best, Galvus® will be as good as Januvia®.
“At worst,” says Close, “safety concerns will mount. Either way, all patients will likely need fairly frequent liver testing—at least over the next few years—as long-term data is compiled. That said, we think the science coming out of Novartis on diabetes is very impressive."
According to the January 18, 2008 Star-Ledger, Joe Jimenez—Novartis’ new pharmaceuticals chief—was quoted as saying Novartis has decided to "step back the U.S. right now" and to focus efforts on launching Galvus® in Europe this year.
Takeda Pharmaceuticals, maker of the TZD drug Actos®, is also developing its own DPP-4 inhibitor. Known as alogliptin, it recently showed itself off at the 67th ADA Scientific Sessions when it came to reducing glucose levels throughout the day. Safety results also found that alogliptin was well tolerated in patients with type 2 diabetes, with an incidence of hypoglycemia similar to placebo. No serious adverse event was reported and no dose-limiting toxicity was observed over the entire dose range.
"These are encouraging early results for alogliptin as a potential new type 2 diabetes treatment to help manage glucose levels throughout the day,” said Qais A. Mekki, MD, PhD, vice president of clinical science at Takeda Global Research & Development, Inc.
Also getting into the “gliptin” game is Bristol-Myers Squibb (BMS), better known as the manufacturer of the popular, type 2 med Glucophage. BMS is currently developing saxagliptin, which is in phase III studies. According to data from the 2007 ADA Scientific Sessions, once-daily doses of saxagliptin for two weeks were safe and well-tolerated without producing hypoglycemia.
Allen King, MD, CDE, FACP, FACE, cofounder and medical director of the Diabetes Care Center in Salinas, California says the DDP-4 inhibitors like Januvia®, alogliptin and saxagliptin are convenient oral med options for people with type 2 diabetes.
“However, Januvia® and the soon-to-be-released products are weak in action and expensive,” says King. “I see their role as in combination with other more potent oral medications such as metformin and thiazolidinediones.”
Another type 2 drug already approved in Europe but not the United States is Acomplia®, also know as rimonabant.
Acomplia®, which, if approved in the United States would be called Zumulti, is indicated to be used alongside diet and exercise for obese people with a body mass index of 30 or greater, as well as for overweight people with a body mass index of 27 or greater who have risk factors for lipid disorders of type 2 diabetes. Manufactured by sanofi-aventis (the maker of Lantus® and Apidra® insulins), Acomplia® is the first, selective, CB1-receptor blocker to be approved for use anywhere in the world. According to sanofi-aventis, CB1-receptor blockade with Acomplia® acts to decrease the “overactivity of the endocannabinoid system.” This system has been shown to play an important role in regulating body weight and in controlling energy balance. According to the Association of the British Pharmaceutical Industry and cited in a 2007 article on www.drugdevelopment-technology.com, sanofi-aventis developed Acomplia® from the knowledge that cannabis (i.e. marijuana) smokers often experience extreme hunger pangs known as "the munchies" after their indulgence. Sanofi-aventis worked on the premise that if cannabinoids stimulate appetite, blocking cannabinoid receptors in the brain might reduce appetite.
According to the February 15, 2006 issue of Journal of the American Medical Association, in phase III clinical studies, 20 mg per day of Acomplia® plus diet for two years promoted “modest but sustained reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors.”
Acomplia® received an approvable letter from the FDA in February 2006, however, it has still yet to receive marketing approval. Kelly Close says the more we learn about this drug, the more qualms we have about its use in patients.
“It's been associated with depression, and given that people with diabetes have a three times higher chance of depression than do their non-diabetic counterparts, this is clearly worrying,” says Close, who adds that Acomplia®'s five-percent weight might seem less and less impressive given the excitement that is coming with other peptides, which have shown approximately 15-percent weight loss in early human testing. Specifically, she cites the combination of the injectable Symlin® and the hormone leptin.
Another promising diabetes drug on the horizon is Pyridorin® (pyridoxamine dihydrochloride), which is being developed by NephroGenex. Pyridorin® is an advanced glycation end product (AGE) inhibitor indicated for the treatment of diabetic kidney disease. Currently in phase II trials, Pyridorin® has shown been shown to be a significant treatment in slowing down diabetic kidney disease.
"Clinical data looks very promising to us so far,” says Close, “and the drug seems to be very well tolerated by most patients—though it is early in its development. There's clearly a need for better drugs to treat complications, given that 30 to 40 percent of diabetes patients experience diabetic kidney disease and the majority of patients with diabetes experience retinopathy, full stop.”
Another drug in clinical trials, mitemcinal, has been found to be an effective remedy for gastroparesis, a stomach disorder that often inflicts people with diabetes. In a 2007 issue of Nature Clinical Practice Gastroenterology & Hepatology, it was found that mitemcinal—an orally administered motilin agonist that accelerates stomach emptying—was effective at improving diabetes-related gastroparesis symptoms.
dLife will continue to keep you abreast of these medications, as well as other potential therapies for diabetes.
NOTE: The information is not intended to be a replacement or substitute for consultation with a qualified medical professional or for professional medical advice related to diabetes or another medical condition. Please contact your physician or medical professional with any questions and concerns about your medical condition.
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