Sitagliptin and Metformin HCl

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important [see CLINICAL PHARMACOLOGY]. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 400 mg per day for periods of up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as indicated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3-to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Use In Specific Populations]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Mechanism Of Action

JANUMET XR

JANUMET XR tablets combine two antidiabetic medications with complementary mechanisms of action to improve glycemic control in adults with type 2 diabetes: sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, and metformin hydrochloride extended-release, a member of the biguanide class.

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which exerts its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and prolonging the action of these hormones. Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. These hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells by intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.

Metformin Hydrochloride

Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects except in certain circumstances [see Use In Specific Populations] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Sitagliptin

In patients with type 2 diabetes, administration of sitagliptin led to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2-to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Sitagliptin And Metformin Hydrochloride Coadministration

In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations, whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Coadministration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear what these findings mean for changes in glycemic control in patients with type 2 diabetes.

In studies with healthy subjects, sitagliptin did not lower blood glucose or cause hypoglycemia.

Cardiac Electrophysiology

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This increase is not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11 times higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

Pharmacokinetics

JANUMET XR

The results of a study in healthy subjects demonstrated that the JANUMET XR (sitagliptin and metformin HCl extended-release) 50 mg/500 mg and 100 mg/1000 mg tablets are bioequivalent to coadministration of corresponding doses of sitagliptin and metformin hydrochloride extended-release.

Bioequivalence between two JANUMET XR 50 mg/500 mg tablets and one JANUMET XR 100 mg/1000 mg tablet was also demonstrated.

After administration of two JANUMET XR 50 mg/1000 mg tablets once daily with the evening meal for 7 days in healthy adult subjects, steady-state for sitagliptin and metformin is reached by Day 4 and 5, respectively. The median Tmax value for sitagliptin and metformin at steady state is approximately 3 and 8 hours postdose, respectively. The median Tmax value for sitagliptin and metformin after administration of a single tablet of JANUMET is 3 and 3.5 hours postdose, respectively.

Absorption

JANUMET XR

After administration of JANUMET XR tablets with a high-fat breakfast, the AUC for sitagliptin was not altered. The mean Cmax was decreased by 17%, although the median Tmax was unchanged relative to the fasted state. After administration of JANUMET XR with a high-fat breakfast, the AUC for metformin increased 62%, the Cmax for metformin decreased by 9%, and the median Tmax for metformin occurred 2 hours later relative to the fasted state.

Sitagliptin

The absolute bioavailability of sitagliptin is approximately 87%. Coadministration of a high-fat meal with sitagliptin had no effect on the pharmacokinetics of sitagliptin.

Distribution

Sitagliptin

The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

Metformin hydrochloride

Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mcg/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Sitagliptin

Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination.

Following a [14C]sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

Metformin hydrochloride

Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion. Metabolism studies with extended-release metformin tablets have not been conducted.

Excretion

Sitagliptin

Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations

Renal Impairment

Sitagliptin

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment with eGFR of 30 to <45 mL/min/1.73 m2, and an approximately 4-fold increase was observed in patients with severe renal impairment including patients with end-stage renal disease (ESRD) on hemodialysis, as compared to normal healthy control subjects.

Metformin hydrochloride

In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS].

Hepatic Impairment

Sitagliptin

In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of sitagliptin. These differences are not considered to be clinically meaningful.

There is no clinical experience in patients with severe hepatic impairment (Child-Pugh score >9).

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.

Gender

Sitagliptin

Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Geriatric

Sitagliptin

When the effects of age on renal function are taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatric

No studies with JANUMET XR have been performed in pediatric patients.

Race

Sitagliptin

Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of available pharmacokinetic data, including subjects of white, Hispanic, black, Asian, and other racial groups.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Body Mass Index (BMI)

Sitagliptin

Body mass index had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Drug Interactions

Sitagliptin And Metformin Hydrochloride

Coadministration of multiple doses of sitagliptin (50 mg) and metformin (1000 mg) given twice daily did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients with type 2 diabetes.

Pharmacokinetic drug interaction studies with JANUMET XR have not been performed; however, such studies have been conducted with the individual components of JANUMET XR (sitagliptin and metformin hydrochloride extended-release).

Sitagliptin

In Vitro Assessment of Drug Interactions

Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.

Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.

In Vivo Assessment of Drug Interactions

Table 4: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs

Coadministered Drug	Dose of Coadministered Drug*	Dose of Sitagliptin*	Geometric Mean Ratio (ratio with/without sitagliptin) No Effect = 1.00
				AUC†	Cmax
No dosing adjustments required for the following:
Digoxin	0.25 mg‡ once daily for 10 days	100 mg‡ once daily for 10 days	Digoxin	1.11§	1.18
Glyburide	1.25 mg	200 mg‡ once daily for 6 days	Glyburide	1.09	1.01
Simvastatin	20 mg	200 mg‡ once daily for 5 days	Simvastatin	0.85¶	0.80
			Simvastatin Acid	1.12¶	1.06
Rosiglitazone	4 mg	200 mg‡ once daily for 5 days	Rosiglitazone	0.98	0.99
Warfarin	30 mg single dose on day 5	200 mg‡ once daily for 11 days	S(-) Warfarin	0.95	0.89
			R(+) Warfarin	0.99	0.89
Ethinyl estradiol and norethindrone	21 days once daily of 35 μg ethinyl estradiol with norethindrone 0.5 mg x 7 days, 0.75 mg x 7 days, 1.0 mg x 7 days	200 mg‡ once daily for 21 days	Ethinyl estradiol	0.99	0.97
			Norethindrone	1.03	0.98
Metformin	1000 mg‡ twice daily for 14 days	50 mg‡ twice daily for 7 days	Metformin	1.02#	0.97
* All doses administered as single dose unless otherwise specified † AUC is reported as AUC0-∞ unless otherwise specified ‡ Multiple dose § AUC0-24hr ¶ AUC0-last # AUC0-12hr

Table 5: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin

Coadministered Drug	Dose of Coadministered Drug*	Dose of Sitagliptin*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUC†	Cmax
No dosing adjustments required for the following:
Cyclosporine	600 mg once daily	100 mg once daily	Sitagliptin	1.29	1.68
Metformin	1000 mg‡ twice daily for 14 days	50 mg‡ twice daily for 7 days	Sitagliptin	1.02§	1.05
* All doses administered as single dose unless otherwise specified † AUC is reported as AUC0-∞ unless otherwise specified ‡ Multiple dose § AUC0-12hr

Table 6: Effect of Metformin on Systemic Exposure of Coadministered Drugs

Coadministered Drug	Dose of Coadministered Drug*	Dose of Metformin*	Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00
				AUC†	Cmax
No dosing adjustments required for the following:
Cimetidine	400 mg	850 mg	Cimetidine	0.95‡	1.01
Glyburide	5 mg	500 mg§	Glyburide	0.78¶	0.63¶
Furosemide	40 mg	850 mg	Furosemide	0.87¶	0.69¶
Nifedipine	10 mg	850 mg	Nifedipine	1.10‡	1.08
Propranolol	40 mg	850 mg	Propranolol	1.01‡	0.94
Ibuprofen	400 mg	850 mg	Ibuprofen	0.97#	1.01#
* All doses administered as single dose unless otherwise specified † AUC is reported as AUC0-∞ unless otherwise specified ‡ AUC0-24hr §GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg ¶Ratio of arithmetic means, p value of difference <0.05 # Ratio of arithmetic means

Table 7: Effect of Coadministered Drugs on Systemic Exposure of Metformin

Coadministered Drug	Dose of Coadministered Drug*	Dose of Metformin*	Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00
				AUC†	Cmax
No dosing adjustments required for the following:
Glyburide	5 mg	500 mg‡	Metformin‡	0.98§	0.99§
Furosemide	40 mg	850 mg	Metformin	1.09§	1.22§
Nifedipine	10 mg	850 mg	Metformin	1.16	1.21
Propranolol	40 mg	850 mg	Metformin	0.90	0.94
Ibuprofen	400 mg	850 mg	Metformin	1.05§	1.07§
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin. [See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Cimetidine	400 mg	850 mg	Metformin	1.40	1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Topiramate	100 mg¶	500 mg¶	Metformin	1.25¶	1.17
* All doses administered as single dose unless otherwise specified †AUC is reported as AUC0-∞ unless otherwise specified ‡GLUMETZA (metformin hydrochloride extended-release tablets) 500 mg §Ratio of arithmetic means ¶ Steady state 100 mg Topiramate every 12 hr + metformin 500 mg every 12 hr. AUC = AUC0-12hr

Clinical Studies

The coadministration of sitagliptin and metformin immediate-release has been studied in patients with type 2 diabetes inadequately controlled on diet and exercise and in combination with other antidiabetic medications.

There have been no clinical efficacy or safety studies conducted with JANUMET XR to characterize its effect on hemoglobin A1c (A1C) reduction. Bioequivalence of JANUMET XR tablets with coadministered sitagliptin and extended-release metformin tablets has been demonstrated for all tablet strengths [see CLINICAL PHARMACOLOGY].

Metformin Extended-Release Compared To Metformin Immediate-Release In Patients With Type 2 Diabetes

In a multicenter, randomized, double-blind, active-controlled, dose-ranging, parallel group trial extended-release metformin 1500 mg once daily, extended-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening), and extended-release metformin 2000 mg once daily were compared to immediate-release metformin 1500 mg per day in divided doses (500 mg in the morning and 1000 mg in the evening). This trial enrolled patients (n = 338) who were newly diagnosed with diabetes, patients treated only with diet and exercise, patients treated with a single anti-diabetic medication (sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, or meglitinides), and patients (n = 368) receiving metformin up to 1500 mg/day plus a sulfonylurea at a dose equal to or less than one-half the maximum dose. Patients who were enrolled on monotherapy or combination antidiabetic therapy underwent a 6-week washout. Patients randomized to extended-release metformin began titration from 1000 mg/day up to their assigned treatment dose over 3 weeks. Patients randomized to immediate-release metformin initiated 500 mg twice daily for 1 week followed by 500 mg with breakfast and 1000 mg with dinner for the second week. The 3-week treatment period was followed by an additional 21-week period at the randomized dose. For HbA1c and fasting plasma glucose, each of the extended-release metformin regimens was at least as effective as immediate-release metformin. Additionally, once daily dosing of extended-release metformin was as effective as twice daily dosing of the immediate-release metformin formulation.

Sitagliptin And Metformin Immediate-Release Coadministration In Patients With Type 2 Diabetes Inadequately Controlled On Diet And Exercise

A total of 1091 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind, placebo-controlled factorial study designed to assess the efficacy of sitagliptin and metformin immediate-release coadministration. Patients on an antihyperglycemic agent (N=541) underwent a diet, exercise, and drug washout period of up to 12 weeks duration. After the washout period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing a 2-week single-blind placebo run-in period. Patients not on antihyperglycemic agents at study entry (N=550) with inadequate glycemic control (A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin immediate-release twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin immediate-release twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Sitagliptin and metformin immediate-release coadministration provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin immediate-release alone, and to sitagliptin alone (Table 8, Figure 1). For patients not on an antihyperglycemic agent at study entry, mean reductions from baseline in A1C were: sitagliptin 100 mg once daily, -1.1%; metformin immediate-release 500 mg bid, -1.1%; metformin immediate-release 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin immediate-release 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin immediate-release 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease in body weight in the groups given sitagliptin in combination with metformin immediate-release was similar to that in the groups given metformin alone or placebo.

Table 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise*

	Placebo	Sitagliptin 100 mg once daily	Metformin Immediate-Release 500 mg twice daily	Metformin Immediate-Release 1000 mg twice daily	Sitagliptin 50 mg bid + Metformin Immediate-Release 500 mg twice daily	Sitagliptin 50 mg bid + Metformin Immediate-Release 1000 mg twice daily
A1C (%)	N = 165	N = 175	N = 178	N = 177	N = 183	N = 178
Baseline (mean)	8.7	8.9	8.9	8.7	8.8	8.8
Change from baseline (adjusted mean†)	0.2	-0.7	-0.8	-1.1	-1.4	-1.9
Difference from placebo (adjusted mean†)      (95% CI)		-0.8‡ (-1.1, -0.6)	-1.0‡ (-1.2, -0.8)	-1.3‡ (-1.5, -1.1)	-1.6‡ (-1.8, -1.3)	-2.1‡ (-2.3, -1.8)
Patients (%) achieving A1C <7%	15 (9%)	35 (20%)	41 (23%)	68 (38%)	79 (43%)	118 (66%)
% Patients receiving rescue medication	32	21	17	12	8	2
FPG (mg/dL)	N = 169	N = 178	N = 179	N = 179	N = 183	N = 180
Baseline (mean)	196	201	205	197	204	197
Change from baseline (adjusted mean†)	6	-17	-27	-29	-47	-64
Difference from placebo (adjusted mean†)      (95% CI)		-23‡ (-33, -14)	-33‡ (-43, -24)	-35‡ (-45, -26)	-53‡ (-62, -43)	-70‡ (-79, -60)
2-hour PPG (mg/dL)	N = 129	N = 136	N = 141	N = 138	N = 147	N = 152
Baseline (mean)	277	285	293	283	292	287
Change from baseline (adjusted mean†)	0	-52	-53	-78	-93	-117
Difference from placebo (adjusted mean†)     (95% CI)		-52‡ (-67, -37)	-54‡ (-69, -39)	-78‡ (-93, -63)	-93‡ (-107, -78)	-117‡ (-131, -102)
* Intent-to-treat population using last observation on study prior to glyburide (glibenclamide) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo.

Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin Immediate- Release, Alone and in Combination in Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise*

Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the healthcare provider.

Sitagliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Immediate-Release Alone

A total of 701 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin immediate-release. Patients already on metformin immediate-release (N=431) at a dose of at least 1500 mg per day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin immediate-release and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin immediate-release (at a dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

In combination with metformin immediate-release, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release (Table 9). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) of Sitagliptin as Add-on Combination

	Sitagliptin 100 mg once daily + Metformin Immediate-Release	Placebo + Metformin Immediate-Releas
A1C (%)	N = 453	N = 224
Baseline (mean)	8.0	8.0
Change from baseline (adjusted mean†)	-0.7	-0.0
Difference from placebo + metformin immediate-release (adjusted mean†) (95% CI)	-0.7‡ (-0.8, -0.5)
Patients (%) achieving A1C <7%	213 (47%)	41 (18%)
FPG (mg/dL)	N = 454	N = 226
Baseline (mean)	170	174
Change from baseline (adjusted mean†)	-17	9
Difference from placebo + metformin immediate-release (adjusted mean†) (95% CI)	-25‡ (-31, -20)
2-hour PPG (mg/dL)	N = 387	N = 182
Baseline (mean)	275	272
Change from baseline (adjusted mean†)	-62	-11
Difference from placebo + metformin immediate-release (adjusted mean†) (95% CI)	-51‡ (-61, -41)
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy and baseline value. ‡ p<0.001 compared to placebo + metformin.

Sitagliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On The Combination Of Metformin Immediate-Release And Glimepiride

A total of 441 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin immediate-release. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin immediate-release (≥1500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue.

Patients receiving sitagliptin with metformin immediate-release and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin immediate-release and glimepiride (Table 10), with mean reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg vs. add-on placebo (+0.4 kg vs. -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia compared to add-on placebo. [See WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

Table 10: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride*

	Sitagliptin 100 mg + Metformin Immediate-Release and Glimepiride	Placebo + Metformin Immediate-Release and Glimepiride
A1C (%)	N = 115	N = 105
Baseline (mean)	8.3	8.3
Change from baseline (adjusted mean†)	-0.6	0.3
Difference from placebo (adjusted mean†) (95% CI)	-0.9‡ (-1.1, -0.7)
Patients (%) achieving A1C <7%	26 (23%)	1 (1%)
FPG (mg/dL)	N = 115	N = 109
Baseline (mean)	179	179
Change from baseline (adjusted mean†)	-8	13
Difference from placebo (adjusted mean†) (95% CI)	-21‡ (-32, -10)
* Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo.

Sitagliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On The Combination Of Metformin Immediate-Release And Rosiglitazone

A total of 278 patients with type 2 diabetes participated in a 54-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin in combination with metformin immediate-release and rosiglitazone. Patients on dual therapy with metformin immediate-release ≥1500 mg/day and rosiglitazone ≥4 mg/day or with metformin immediate-release ≥1500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin immediate-release ≥1500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18.

In combination with metformin immediate-release and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release and rosiglitazone (Table 11) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population. Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 11: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin Immediate-Release and Rosiglitazone*

	Week 18
	Sitagliptin 100 mg + Metformin Immediate-Release + Rosiglitazone	Placebo + Metformin Immediate-Release + Rosiglitazone
A1C (%)	N = 176	N = 93
Baseline (mean)	8.8	8.7
Change from baseline (adjusted mean†)	-1.0	-0.4
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean†) (95% CI)	-0.7‡ (-0.9, -0.4)
Patients (%) achieving A1C <7%	39 (22%)	9 (10%)
FPG (mg/dL)	N = 179	N = 94
Baseline (mean)	181	182
Change from baseline (adjusted mean†)	-30	-11
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean†) (95% CI)	-18‡ (-26, -10)
2-hour PPG (mg/dL)	N = 152	N = 80
Baseline (mean)	256	248
Change from baseline (adjusted mean†)	-59	-21
Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean†) (95% CI)	-39‡ (-51, -26)
* Intent-to-treat population using last observation on study prior to glipizide (or other sulfonylurea) rescue therapy. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡ p<0.001 compared to placebo + metformin + rosiglitazone.

Sitagliptin Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On The Combination Of Metformin Immediate-Release And Insulin

A total of 641 patients with type 2 diabetes participated in a 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin immediate-release. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin immediate-release (≥1500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin. After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin (N=229) or placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

Among patients also receiving metformin immediate-release, the median daily insulin (pre-mixed, intermediate or long acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the study. Patients receiving sitagliptin with metformin immediate-release and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin immediate-release and insulin (Table 12). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin immediate-release and insulin and -0.2 kg in patients receiving placebo with metformin immediate-release and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release and Insulin*

	Sitagliptin 100 mg + Metformin Immediate-Release + Insulin	Placebo + Metformin Immediate-Release + Insulin
A1C (%)	N = 223	N = 229
Baseline (mean)	8.7	8.6
Change from baseline (adjusted mean†, ‡ )	-0.7	-0.1
Difference from placebo (adjusted mean†) (95% CI)	-0.5§ (-0.7, -0.4)
Patients (%) achieving A1C <7%	32 (14%)	12 (5%)
FPG (mg/dL)	N = 225	N = 229
Baseline (mean)	173	176
Change from baseline (adjusted mean†)	-22	-4
Difference from placebo (adjusted mean†) (95% CI)	-18§ (-28, -8.4)
2-hour PPG (mg/dL)	N = 182	N = 189
Baseline (mean)	281	281
Change from baseline (adjusted mean†)	-39	1
Difference from placebo (adjusted mean†) (95% CI)	-40§ (-53, -28)
* Intent-to-treat population using last observation on study prior to rescue therapy. † Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate-or long-acting]), and baseline value. ‡ Treatment by insulin stratum interaction was not significant (p>0.10). § p<0.001 compared to placebo.

Sitagliptin Add-On Therapy Vs. Glipizide Add-On Therapy In Patients With Type 2 Diabetes Inadequately Controlled On Metformin Immediate-Release

The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes. Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin immediate-release monotherapy (dose of ≥1500 mg per day) which included washout of medications other than metformin immediate-release, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control. Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg.

After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 13). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the study (over 70% of patients had baseline A1C <8% and over 90% had A1C <9%).

Table 13: Glycemic Parameters in a 52-Week Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Intent-to-Treat Population) *

	Sitagliptin 100 mg + Metformin Immediate-Release	Glipizide + Metformin Immediate-Release
A1C (%)	N = 576	N = 559
Baseline (mean)	7.7	7.6
Change from baseline (adjusted mean†)	-0.5	-0.6
FPG (mg/dL)	N = 583	N = 568
Baseline (mean)	166	164
Change from baseline (adjusted mean†)	-8	-8
* The intent-to-treat analysis used the patients' last observation in the study prior to discontinuation. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.

Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Per Protocol Population)*

The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. +1.1 kg).