Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a global epidemic with increasing impact on individuals and healthcare providers. Available treatments (such as metformin, sulfonylureas, glitazones, and insulin) have proven unsatisfactory in producing a long-lasting impact on glycemic control. In addition, most of these treatments have undesirable side effects such as weight gain and hypoglycemia. As a result, exploring new treatment targets and new therapies is mandatory in order to treat this condition. The incretin pathway, in particular glucagon-like peptide (GLP-1), plays an important pathological role in the development of T2DM, and treatments targeting the incretin system have recently become available. These can mainly be divided into two broad categories; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase-4 (DPP-4; the enzyme responsible for rapid inactivation of incretins) inhibitors (sitagliptin, vildagliptin). Saxagliptin is a novel DPP-4 inhibitor that has recently completed phase 3 studies. Saxagliptin is a potent and specific inhibitor of DPP-4 (in comparison with other dipeptidyl peptidase enzymes) that is given once daily. Current data suggest that saxagliptin as monotherapy or in combination with metformin, glyburide, or a glitazone results in significant reductions in fasting and postprandial plasma glucose and hemoglobin A(1c) (HbA(1c)). Saxagliptin is well tolerated and does not increase hypoglycemia compared with the placebo, and is probably weight neutral. Saxagliptin will be a new effective drug in the currently available variety of antidiabetic medications for patients with T2DM.

Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats

“…A pathophysiologic relationship between reduced nitric oxide (NO) bioavailability and loss of insulin synthesis 5) . Saxagliptin is a dipeptidyl peptidase-4 (DPP4) inhibitor that causes significant reductions in postprandial plasma glucose and hemoglobin A1C levels 6,7) . Inhibition of DPP4 increases the half-life and circulating levels of intact (active) glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide, which improve postprandial glucose clearance by stimulating pancreatic insulin release and inhibiting hepatic glucose release 8) .…”

Saxagliptin a New Second Line Therapy After Metformin for the Treatment of Type 2 Diabetes

“…Both saxagliptin and its metabolite are highly selective (4000-fold) for inhibition of DPP-4 compared with a range of other proteases. 67 Systemic exposure to saxagliptin has been shown to be dose proportional, and pharmacokinetic parameters to be similar in patients with T2DM and in healthy individuals. Saxagliptin inhibits DPP-4 at doses between 2.5 and 400 mg, with doses greater than 150 mg providing the same maximal inhibition.…”

“…70 In addition, Saxagliptin has been shown to improve surrogate markers of β-cell function in patients with T2DM. 67 The efficacy of saxagliptin in patients with T2DM from published RCTs (randomised controlled trials), including saxagliptin monotherapy and combination therapy with sulphonylureas or metformin is summarized in Table 1. [71][72][73][74][75] Saxagliptin has also been examined in combination with TZD in a study of 565 patients with inadequate glycemic control (HbA 1c 7.0%-10.5%).…”

“…No significant pharmacodynamic interactions were found between saxagliptin or its metabolite and simvastatin, magnesium and aluminim hydroxides plus simethicone, famotidine, omeprazole, digoxin, metformin, glyburide or pioglitazone. 67,70,86,87 Significant drug interactions were found when saxagliptin was coadministered with ketoconazole and diltiazem, therefore, dose adjustments may be required. 67,70 …”

“…67,70,86,87 Significant drug interactions were found when saxagliptin was coadministered with ketoconazole and diltiazem, therefore, dose adjustments may be required. 67,70 …”