Sylvester O. Agbahiwe, PharmD, BCACP, and Chika Obi, PharmD Candidate
Kazano (alogliptin/metformin) is a dipeptidyl-peptidase-4 (DPP-4) inhibitor and a biguanide combination in a single tablet indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). As the most common form of the disease, T2DM affects roughly 24 million people and accounts for more than 90% of diabetes cases diagnosed in the United States.1
It is a progressive and chronic condition that can lead to serious complications, including heart disease, blindness, and nerve and kidney damage. According to the International Diabetes Federation, the global health care expenditures for type 1 diabetes mellitus and T2DM were estimated to be $471.6 billion in 2012, and these expenditures are projected to exceed $595 billion by the year 2030.1
Mechanism of Action/ Pharmacology
Alogliptin is a DPP-4 inhibitor that is designed to slow the inactivation of the incretin hormones glucagon- like peptide-1 and glucose-dependent insulinotropic peptide, thereby increasing their bloodstream concentrations. This enables the pancreas to secrete insulin in a glucose-dependent manner, thus reducing fasting and postprandial glucose concentrations. Metformin is a biguanide that decreases hepatic glucose production and intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.2-4
The coadministration of alogliptin and metformin has been studied in patients with T2DM inadequately controlled on either diet or exercise alone, metformin alone, or metformin in combination with a thiazolidinedione. The safety and efficacy of Kazano were demonstrated in 4 clinical trials involving more than 2700 patients with T2DM. Results from studies showed that when alogliptin was coadministered with metformin, patients experienced significant improvements in their glycemic control compared with monotherapy. In a 26-week, double- blind, placebo-controlled study involving patients inadequately controlled on diet and exercise alone, Kazano resulted in additional reductions in glycated hemoglobin (A1C) of 1.0% over alogliptin alone and 0.5% over metformin alone. In a 26-week placebo-controlled study of alogliptin administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the Kazano group versus 2.9% in the placebo treatment group.
In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin were randomized to receive either the addition of once-daily alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg). In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and fasting plasma glucose compared with the titration of pioglitazone from 30 to 45 mg at week 26 and at week 52.5-7
Kazano (alogliptin and metformin HCl 12.5 mg/500 mg and 12.5 mg/1000 mg) should be taken twice daily with food. The dose may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg of alogliptin and 2000 mg of metformin. Alogliptin is 100% bioavailable (metformin is 50% to 60% bioavailable) with a 21-hour elimination half-life. It does not undergo extensive metabolism; 76% is excreted in the urine.2-4
Contraindications, Warnings, and Precautions
Common adverse reactions (≥4%) reported with Kazano include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infections. Kazano is contraindicated in patients with a history of serious hypersensitivity reactions to any of the components of these products, patients with renal impairment (serum creatinine ≥1.5 mg/dL in men, ≥1.4 mg/dL in women, or abnormal creatinine clearance), or patients with acute or chronic metabolic acidosis. Kazano carries a black box warning for lactic acidosis, a buildup of lactic acid in the bloodstream, associated with metformin use. The FDA is requiring 2 postmarketing studies to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions, as well as a pediatric safety and efficacy study. Kazano is Pregnancy Category B; however, whether Kazano is distributed in breast milk is unknown.2-4
Dr. Agbahiwe is clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. Ms. Obi is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences.
References (updated since publication of the print edition)
International Diabetes Federation website. www.idf.org/diabetesatlas. Accessed December 4, 2013.
Lexicomp website. www.lexi.com. Accessed November 20, 2013.
McAuley D. KAZANO (alogliptin and metformin HCl) tablet, film coated. Global RPH, 02 Feb 2013. www.globalrph.com/drug_kazano.htm. Accessed December 1, 2013.
Highlights of prescribing information. Dailymed website. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=83cb7914-a683-47bb-a713-f2bc6a596bd2. Accessed December 1, 2013.
Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63(1):46-55.
Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011;13(12):1088-1096.
Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Obes Metab. 2014;16(1):30-37.