Drug Topics - October 13, 2008 - (Page 7s)

DRUG TOPICS 7s Saxagliptin, another DPP-4 inhibitor, is under joint investigation by Bristol Myers Squibb and AstraZeneca for the treatment of type 2 diabetes. Results from a 24-week, multicenter, randomized, doubleblind Phase II study in treatmentnaïve patients with HgA1c from greater than or equal to 7 percent to less than or equal to 10 percent demonstrated that 35 percent, 38 percent, and 41 percent of the patients who received saxagliptin (2.5mg, 5mg, or 10mg, respectively) achieved an HgA1c of less than 7 percent, compared to 24 percent of the patients receiving placebo (P<0.05 for 5mg and 10mg). Saxagliptin also showed significant reductions compared to placebo in FPG and PPG from baseline to week 24. In its adverse-event profile, Saxagliptin was similar to placebo, with upper respiratory tract infections (8.8 percent), headache (8.2 percent), and urinary tract infections (6.9 percent) the most common adverse events reported. Saxagliptin was not associated with any weight gain in any of the groups. GLP-1 analogues For treatment of type 2 diabetes, GLP1 analogues present another option for clinicians. GLP-1 analogues lower glucose in Type 2 diabetics, while offering a unique advantage: With GLP-1 analogues, glucose levels stop going down when they reach a normal range. Exenatide (Byetta, from Eli Lilly and Co. and Amylin Pharmaceuticals Inc.), the first GLP-1 approved for treatment of type 2 diabetes, has been used clinically in the United States since April 2005. “Exenatide promotes satiety, delays gastric emptying, promotes glucose-mediated insulin secretion, and inhibits post-prandial glucagon secretion. The drug may increase beta-cell mass, but the clinical significance of this finding remains speculative," Ponte said. "An important benefit from its use is weight loss, an advantage in the mostly overweight or obese person with type 2 diabetes, and no propensity to cause hypoglycemia.” Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who are taking metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, or a thiazolidinedione but have not achieved adequate glycemic control. Exenatide resists degradation by DPP-4 and has a half-life of 12 to 14 hours, thus requiring twice-daily subcutaneous administration 60 minutes before the morning and evening meals. Of greater concern, he continued, were “thirty case reports of pancreatitis with the drug, which led to labeling changes in 2007. Although cause and effect have not been established, such reports may undermine the confidence of prescribers and patients who would consider using the drug. Liraglutide (Novo Nordisk) is a once-daily GLP-1 analogue that has been studied in more than 4000 patients. The LEAD program (Liraglutide Effect and Action in Diabetes) was composed of five (four 26-week and one 52week) randomized, controlled, doubleblind studies that examined the use of liraglutide as an adjunct to diet and exercise, both as monotherapy and in combination with glimepiride, metformin, or rosiglitazone. The LEAD 3 study, a 52week study that compared the safety and efficacy of liraglutide 1.2mg and 1.8 mg daily to glimepiride 8mg when used as monotherapy, showed that liraglutide 1.2mg and 1.8 mg reduced HgA1c significantly more than did glimepiride (P=0.0014 and P<0.0001, respectively). Hoffmann-La Roche Inc. and Ipsen Inc. are working on the development of taspoglutide, a weekly GLP-1 analogue. The results of an eight-week study presented at the ADA showed that taspoglutide 5mg, 10mg, and 20 mg taken weekly significantly improved HgA1c compared to placebo. Also, patients treated with taspoglutide 10mg and 20 mg had significant body weight reductions from baseline. The most commonly reported adverse event was mild to moderate nausea, which was dosedependent. The results of the study support the entry of taspoglutide to Phase III studies. SGLT-2 inhibitors SGLT-2 inhibitors are another new class of medications currently in clinical development for the treatment of type 2 diabetes. SGLT-2, which is expressed exclusively in the S1 segment of the proximal tubule, is a co-transporter responsible for about 90 percent of glucose reabsorption. “SGLT-2 inhibitors promote glycosuria by blocking the reabsorption of glucose in the proximal tubule of the kidney," Ponte said. "This approach to managing diabetes is totally unique, because it does not target the three major defects associated with type 2 diabetes, namely defective insulin secretion, increased hepatic glucose output, and insulin resistance.” Preliminary results from a Phase 2a study presented at ADA 2007 showed that dapagliflozin (BristolMyers Squibb Co. and AstraZeneca) increased urinary glucose excretion in type 2 diabetics. These findings have been extended in a three-month Phase IIb study of 389 treatment-naïve patients with type 2 diabetes who were randomized to treatment with dapagliflozin, placebo, or extended-release metformin. Dapagliflozin demonstrated significant reductions compared to placebo in FPG and HgA1c.

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Drug Topics - October 13, 2008 Contents Latebreakers Letters Kansas Pharmacists Partner with Law Enforcement to Fight Meth Use Pharmacy Board to Oversee Med Distribution at West Virginia Free Clinics Rx Care JP�at Large Celebrating Community Special Report Self-Care Government and Law Newer Treatment Option for Type 2 Diabetes New Products Advertisers Index Technology Classified Viewpoint:�Pharmacists Must Change our Ways

Drug Topics - October 13, 2008

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