Previous medication therapies for diabetes were limited to insulin, sulfonylureas, and metformin. Promising new approaches include DPP-IV inhibitors, GLP-1 analogues, and SGLT-2 inhibitors.
Diabetes is one of the world's fastest-growing diseases. The World Health Organization (WHO) expects that there will be more than 360 million diabetics by 2030, with type 2 diabetes accounting for 90 to 95 percent of all cases.
The development of new classes of drugs, such as dipeptidyl peptidase-IV (DPP-IV) inhibitors, glucagon-like peptide-1 (GLP-1) analogues, and renal sodium-glucose transporter-2 (SGLT-2), to supplement older therapies, including lifestyle-directed interventions, insulin, sulfonylureas, and metformin, is increasing the treatment options for type 2 diabetes.
Januvia (sitagliptin), from Merck and Co., was the first DPP-IV inhibitor approved by the Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. "It is a unique agent, different from any other oral class of antidiabetic agents, which has the advantage of once-daily administration and a low propensity for drug interactions. This is important, since persons with diabetes are often on multiple drugs to manage concomitant hypertension, dyslipidemia, heart disease, and other diabetes-related complications," said Charles D. Ponte, PharmD, BC-ADM, BCPS, CDE, FAPhA, FASHP, FCCP, professor of clinical pharmacy and family medicine, Robert C. Byrd Health Sciences Center Schools of Pharmacy and Medicine at West Virginia University.
In two double-blind, randomized, placebo-controlled studies (of 18 and 24 weeks' duration), daily treatment with 100 milligrams (mg) Januvia provided significant improvements in hemoglobin (Hg)A1C, fasting plasma glucose (FPG), and two-hour post-prandial glucose (PPG) compared to placebo (P<0.001). In both studies, patients treated with Januvia had no increase in body weight; patients given placebo had a small reduction.
The efficacy of Januvia in combination with metformin was assessed in 701 patients with type 2 diabetes in a 24-week, randomized, double-blind, placebo-controlled study. In combination with metformin, Januvia provided significant improvements in HgA1C, FPG, and two-hour PPG when compared to placebo with metformin (P<0.001).
In January of 2008, Takeda Pharmaceutical Co. Ltd. submitted a new drug application (NDA) for alogliptin for the treatment of type 2 diabetes. Results from five pivotal Phase III studies of alogliptin were presented at the 68th Scientific Session of the American Diabetes Association (ADA). The Phase III studies were randomized, double-blind, placebo-controlled studies, designed to assess the efficacy and safety of alogliptin 12.5 mg and 25 mg once daily, alone or when added to metformin, pioglitazone, insulin, or glyburide.
The primary endpoint was the change from baseline in HgA1c at week 26 (or last observation). In all five studies, there was a significant reduction in HgA1c from baseline to week 26 compared to placebo (P<0.001) for both the 12.5mg and 25mg doses.
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, double-blind Phase II study in treatment-naïve 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.