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. The original FDA assessment of Sitagliptin in 2006 can also be reviewed as can the FDA PI History of Label Changes. 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 and metformin therapy and not at goal-switch to a GLP-1R agonist or add a GLP-1R agonist? This question was examined in a randomized placebo controlled 16 week trial. Violante and colleagues reported the results of a 20 week study comparing patients not achieving goal on sitagliptin plus metformin (mean A1c of 7.9%) who switched sitagliptin (n=127) for exenatide vs adding exenatide to sitagliptin plus metformin (n=128). More patients switching to exenatide discontinued due to adverse events. This trial A Comparison of Adding Exenatide With Switching to Exenatide in Patients With Type 2 Diabetes Experiencing Inadequate Glycemic Control With Sitagliptin Plus Metformin was initially reported on Clinical Trials.gov. Addition of exenatide to sitagliptin was associated with 0.3% greater reduction in A1c (non-inferior according to predefined criteria) compared to switching of sitagliptin to exenatide. Sitagliptin plus exenatide (0.68% reduction in A1c) was better tolerated relative to exenatide (0.38%) alone. More patients achieved a target A1c on exenatide plus sitagliptin (44.3%) compared to exenatide alone (29.5%). There was no significant difference in body weight in the 2 treatment groups. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with Type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin Diabet Med. 2012 Feb 29. doi: 10.1111/j.1464-5491.2012.03624.x

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]

           Sitagliptin and insulin combination therapy

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.

A second study compared the effects of adding sitagliptin or exenatide to patients (~16 per group, duration of diabetes only 5-6 years) not achieving adequate glucose control on metformin plus insulin glargine. There was a 4-8 week run in period to establish insulin glargine therapy in all patients at bedtime, with titration of dose to a fasting glucos eof 5.6 mM. Subjects were then randomized to continue on insulin/metformin alone, or either exenatide or sitagliptin was added, for a total of 4 weeks. The primary outcome was 6 hrs PPG following a standard breakfast. Baseline HbA1c was 7.9% in the insulin alone or insulin plus sitagliptin group and 8.4% in the insulin plus exenatide group. Both sitagliptin and exenatide improved PPG to a similar extent after 4 weeks, with a greater HbA1c reduction in the exenatide group which started from a higher baseline. However, more patients in the sitagliptin group achieved a HbA1c of less than 7%. Fewer patients reported hypoglycemia on sitagliptin compared to exenatide and more AEs were reported on exenatide. No serious hypoglycemia was observed. Further improvement in postprandial glucose control when adding exenatide (EXE) or sitagliptin (SITA) to combination therapy with insulin glargine (GLAR) and metformin (MET) - a proof-of-concept study. Diabetes Care. 2010 Mar 31. [Epub ahead of print]

A subsequent group of patients not achieving glycemic control on metformin plus another OAD, including SUs, were randomized to receive either sitagliptin plus insulin detemir, or sitagliptin plus SU therapy, for 26 weeks, after discontinuation of other OADs. Tthe dose of insulin detemir was titrated by the investigator according to fasting plasma glucose targets. Mean starting HbA1c at baseline was 8.5%. Subjects treated with insulin detemir had a reduction in A1c of 1.4% vs. a 0.89% reduction in subjects treated with SU, on the sitagliptin/metformin background and more insulin-treated subjects achieved a HbA1c of less than 7% compared to SU-treated patients (45 vs. 24%). Body weight decreased in both patient populations despite the improvement in A1c, and no significant differences or increases in hypoglycemia rates were observed despite the improvements in A1c. See Efficacy and safety of insulin detemir once-daily in combination with sitagliptin and metformin: the Transition(™) randomised controlled trial. Diabetes Obes Metab. 2010 Dec 3. doi: 10.1111/j.1463-1326.2010.01351.x

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]

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):55-72and 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]Subjects with T2DM treated with sitagliptin on a metformin background for 4 weeks exhibited a significant increase in circulating endothelial progenitor cells, in association with increased plasma levels of SDF-1a by 50%and decreased levels for the proinflammatory cytokine MCP-1. Endothelial cells were defined as CD34+KDR+ cells by flow cytometry. There was a negative correlation between plasma glucose and circulating levels of EPCs, hence whether the change is actually due to sitagliptin or improved glucose control cannot be ascertained The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes mellitus. Possible role of stromal derived factor-1{alpha} Diabetes Care. 2010 Mar 31. [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]