Sitagliptin, also known as Januvia, was approved for the treatment of type 2 diabetes in the United States on October 17 2006. Sitagliptin was approved for use either as monotherapy, or as combination therapy when added to either metformin, a sulphonylurea, or a thiazolidinedione (PPARg agonist) such as rosiglitazone or pioglitazone. The usual dose is 100 mg daily, however patients with renal impairment may require a reduction in dose to either 50 mg or 25 mg. Information on Sitagliptin Prescribing Information for patients or for Sitagliptin (Januvia) Prescribing Information for Physicians is now available, and more background information can be found at www.januvia.com. A fixed dose metformin-sitagliptin combination to be administered twice daily (containing either 500 mg or 1000 mg metformin as well as 50 mg sitagliptin per tablet ), known as Janumet, has also been approved in the United States as of March 30 2007. View the Janumet Press Release or Janumet Prescribing Information.
Initial pricing information in the United States indicates that a 100 mg tablet of Januvia will cost $4.86, as described in the Januvia FDA Approval Press Release from Merck.
The efficacy of sitagliptin as monotherapy at doses of 100 or 200 mg once daily was studied in a 24 week trial, resulting in placebo-subtracted reductions in A1C of -0.79 and -0.94%, respectively. Sitagliptin also improved β-cell function as assessed by HOMA and proinsulin:insulin ratios. Sitagliptin was well tolerated and weight neutral, as outlined in Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006 Dec;29(12):2632-7
The efficacy of sitagliptin was also assessed in subjects who were not achieving adequate glycemic control on at least 1500 mg of metformin alone (mean HbA1c of 8%). Sitagliptin therapy for 24 weeks produced an additional improvement in HbA1c of 0.65%, and 47% of patients achieved a HbA1c of less than 7%. See Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006 Dec;29(12):2638-43
Sitagliptin was also assessed as add on combination therapy in patients not adequately controlled with a HbA1c between 7-10% on Pioglitazone for at least 8-14 weeks. At the time of randomization, all patients were receiving either 30 or 45 mg of pioglitazone. The mean HbA1c at the start of the study was 8.1% and after 24 weeks of therapy, sitagliptin produced a mean reduction in HbA1c of 0.7% and a reduction in fasting glucose of about 1 mM. The mean end of study HbA1c was 7.2 vs 7.8% and the percent of patients at less than 7% was 45.4 vs. 23% for sitagliptin plus pioglitazone vs pioglitazone alone, respectively. Adverse events leading to discontinuation were slightly higher in the sitagliptin group (5.7 vs 1.1 %). Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006 Oct;28(10):1556-68.
In contrast, sitagliptin has also been studied together with metformin as initial combination therapy for the treatment of T2DM. In a 24 week study, combination therapy of sitagliptin/metformin was significantly more efficacious than use of either drug as monotherapy alone, and was well tolerated. The proportion of patients achieving an HbA1c of <7% and <6.5% was 66% and 44%, respectively, in the sitagliptin 100 mg/Metformin 2000 mg group .See Effect of Initial Combination Therapy with Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, and Metformin on Glycemic Control in Patients with Type 2 Diabetes. Diabetes Care. 2007 May 7; [Epub ahead of print]
Sitagliptin therapy has been examined in a 24 week study in human subjects with T2DM (baseline HbA1c 7-5-10.5%) not achieving adequate glycemic control on either glimepiride alone or on glimepiride and metformin. Patients on glimepiride plus metformin treated with sitagliptin experienced a reduction in HbA(1c) of 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on glimepiride plus sitagliptin alone. Hypoglycemia and body weight gain were more common in patients treated with sitagliptin. See Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007 Jun 26; [Epub ahead of print]
The efficacy and safety of sitagliptin (65 subjects) in patients with type 2 diabetes (initial A1c 6-5-10%) and chronic renal insufficiency was examined over 52 weeks in subjects with moderate (creatinine clearance >30 and <50 ml/min; dose of sitagliptin was 50 mg daily) or severe (creatinine clearance <30 ml/min; dose of sitagliptin was 25 mg daily). Sitagliptin treatment was associated with a reduction in HbA1c of 0.7% with less hypoglycemia reported than in subjects receiving glipizide (4.6 vs 23.1% respectively). There were 5/65 deaths in the sitagliptin-treated group vs 1/26 in the placebo/glipizaide group. Cardiovascular AEs were similar in the treatment groups after adjustment for drug exposure over time. See Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008 Jun 1. [Epub ahead of print]
In patients not achieving therapeutic goals on pioglitazone (HbA1c more than 7.5%) metformin and sitagliptin produced comparable reductions in HbA1c over 52 weeks although patients on metformin received less pioglitazone (15 mg) compared to those treated with sitagliptin (30 mg). Metformin therapy was associated with less weight gain and enhanced insulin sensitivity Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients. Metabolism. 2009 Dec 14. [Epub ahead of print]
The combination of sitagliptin and insulin, with or without metformin, vs, placebo plus insulin, was studied in 322 subjects not adequately controlled on insulin with a mean baseline HbA1c of 8.7% (range 7.5-11%). Subjects were receiving a variety of insulin therapies, including long-acting, intermediate acting, and insulin mixes. The dose of insulin was fixed over the 24 week study period. Addition of sitagliptin was associated with a mean reduction in hbA1c of 0.6%, however only 13% of sitagliptinn-treated subjects achieved a mean HbA1c of less than 7%. Sitagliptin therapy was also associated with a greater incidence of hypoglycemia See Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes Diabetes Obes Metab. 2010 Feb;12(2):167-77.
Treatment of patients with T2DM (mean baseline HbA1c 8.1%, range of 7-10%) with sitagliptin as the only therapeutic agent for 18 weeks at doses of 100 or 200 mg a day produced significant reductions of HbA1c (0.68-0.48%), improvement of β-cell function (HOMA-B, proinsulin;insulin ratio), with no significant adverse events and no change in body weight. No differences were seen in patients treated with either 100 or 200 mg daily. Eligible patients were on no prior therapy, or one or 2 oral agents which were washed out for up to 12 weeks before randomization. Mean duration of diabetes was 4.5 years, baseline mean entry HbA1c was 8.1% and 88.9% of patients completed the 18 week study period. Patients with a mean duration of diabetes of less than 3 years had relatively greater reductions in HbA1c. More patients on sitagliptin achieved a HbA1c less than 7% (29-36%) compared to placebo (16%). See Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006 Sep 26; [Epub ahead of print]
The efficacy of sitagliptin monotherapy was examined in 12 week placebo-controlled studies in 151 Japanese subjects with T2DM, mean starting HbA1c of 6.5-10.5%. Sitagliptin 100 mg once daily fasting and postprandial glucose and reduced HbA1c by 0.65% after 12 weeks with no weight gain and no major side effects. See Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract. 2007 Oct 12; [Epub ahead of print]
An eight week study of sitagliptin therapy in patients with IGT revealed little effect of sitagliptin on either fasting or postprandial glucose or insulin levels The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose Clin Endocrinol (Oxf). 2009 Dec 18. [Epub ahead of print]
The pharmacokinetic profiles of sitagliptin in healthy human subjects have been described after single oral dosing. Sitagliptin is cleared via the kidney, exhibits a half life of 8-12 hours, and a single dose of 100 mg produces long lasting DPP-4 inhibition over a 24 hr period. See Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005 Dec;78(6):675-88. The majority (74%) of sitagliptin is eliminated without being metabolized in human subjects, via the kidney, with a small amount detected in the GI tract METABOLISM AND EXCRETION OF THE DPP-4 INHIBITOR [14C]SITAGLIPTIN IN HUMANS. Drug Metab Dispos. 2007 Jan 12; [Epub ahead of print]
Similarly, the PK-PD relationships for sitagliptin administration (multiple doses) and plasma DPP-4 activity together with plasma meal-stimulated GLP-1 responses in healthy human subjects were described in Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006 Jan;28(1):55-72. and in Pharmacokinetics and Pharmacodynamic Effects of the Oral DPP-4 Inhibitor Sitagliptin in Middle-Aged Obese Subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86. At doses greater than 100 mg daily, DPP-4 inhibition 24 h following the last dose is generally greater than or equal to 80%. Sitagliptin therapy increased meal-stimulated plasma active GLP-1 levels about 2-fold in healthy male volunteers. Intriguingly, values of total GLP-1 were actually modestly reduced after 10 days of sitagliptin therapy. No changes in the levels of IGF-1 or IGF-BP3, putative DPP-4 substrates, were observed in this study. Similar results, namely increases in postprandial levels of GLP-1 and GIP, were obtained in studies of single oral dosing of sitagliptin, 25 or 200 mg, as outlined in Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels following an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006 Aug 15; [Epub ahead of print]
NPY is a putative DPP-4 substrate, and potentiation of NPY activity may result in increased blood pressure in specific situations, such as when exogenous NPY is co-infused with angiotensin-II, or in the setting of sympathetic nerve stimulation in rats together with A-II infusion as outlined in Hypertension. 2008 Apr 28. [Epub ahead of print] There is little evidence that DPP-4 inhibitors produce significant effects on blood pressure in long term clinical studies. Short term studies in non-diabetic patients did not reveal any effect of sitagliptin on blood pressure in hypertensive subjects Effect of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, on Blood Pressure in Nondiabetic Patients With Mild to Moderate Hypertension J Clin Pharmacol. 2008 Mar 19; [Epub ahead of print]
Clinical and preclinical data for sitagliptin was presented at the 2006 Annual Meeting of the American Diabetes Association in Washington as outlined in ADA 2006 Sitagliptin Abstracts
In Abstract 633-P, Sitagliptin was described as a competitive, reversible inhibitor of DPP-4 (ICµ50? = 17 nM, Kµi? = 9 nM) that is highly selective over all proteases tested (ICµ50?s > 50 µM), including FAP, QPP, DPP8, DPP9, PEP, APP, and prolidase. In lean mice, single oral doses of MK-0431 reduced blood glucose excursion following an OGTT in a dosage-dependent manner from 0.1 mg/kg PO (23% reduction) to 3.0 mg/kg PO (55% reduction). The reduction of blood glucose excursion following a dose of 3 mg/kg corresponded to a peak plasma drug concentration of approximately 600 nM, 96% inhibition of plasma DPP-4 activity, and a 2 to 3-fold increase in circulating active GLP-1. The increase in GLP-1 was analogous to what is observed upon glucose challenge in DPP-4 deficient mice. In insulin resistant mice with diet-induced obesity, a dose dependent (0.3, 3, 30 mg/kg PO) decrease in blood glucose excursion was also observed following oral glucose administration. Maximal reduction in glucose excursion was seen at the 3 mg/kg dose, corresponding to a peak plasma drug concentration of approximately 700 nM. The compound has demonstrated oral bioavailability in mice, rats, dogs, and monkeys of 61, 76, 100, and 68%, respectively, and a half-life ranging from 1-5 hours.
Phase 1 testing of MK-0431 was reported in Abstract 353-OR. A randomized, placebo-controlled, 3-period, crossover study was conducted in 56 patients with T2D on diet exercise treatment to assess the glucose lowering activity as well as the safety and tolerability of single oral doses of MK-0431. Patients received single oral doses of 25-mg or 200-mg MK-0431 or placebo, separated by 7-day washout intervals. Following an overnight fast, patients had an oral glucose tolerance test (OGTT) at 2 hours post dose. MK-0431 was generally well tolerated and associated with a significant reduction of glycemic excursion following the OGTT: incremental glucose AUC was reduced by approximately 22% (p< 0.001) and 26% (p< 0.001), for the 25- and 200-mg doses respectively, as compared to placebo. Both doses were associated with approximately 2-fold increases in active GLP-1 levels as well as the ratio of active to total GLP-1 levels following an OGTT (p<0.001), as compared to placebo. Doses of 25- and 200-mg were associated with increases in plasma insulin AUC (22% and 23% respectively, p<0.001), plasma c-peptide AUC (13% and 21% respectively, p<0.001) and reductions in plasma glucagon AUC (8%, p=0.015 and 14%, p<0.001 respectively), following the OGTT, as compared to placebo.