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Juvisync

"The U.S. Food and Drug Administration today approved three new related products for use with diet and exercise to improve blood sugar control in adults with type 2 diabetes: Nesina (alogliptin) tablets, Kazano (alogliptin and metformin hydrochlor"...

Juvisync

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sitagliptin

Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are increased by JUVISYNC, 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, JUVISYNC 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.

Simvastatin

Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces VLDL and TG and increases HDL-C.

Pharmacodynamics

Sitagliptin

General

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.

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 how these findings relate to 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 was observed at 3 hours postdose and 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.

Simvastatin

Epidemiological studies have demonstrated that elevated levels of total-C, LDL-C, as well as decreased levels of HDL-C are associated with the development of atherosclerosis and increased cardiovascular risk. Lowering LDL-C decreases this risk. However, the independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Pharmacokinetics

General

JUVISYNC

The results of bioequivalence studies in healthy subjects demonstrated that JUVISYNC (sitagliptin and simvastatin) is bioequivalent to coadministration of sitagliptin and simvastatin as individual tablets.

Sitagliptin and simvastatin do not have a clinically meaningful pharmacokinetic interaction.

Absorption

JUVISYNC

A high-fat breakfast did not affect sitagliptin exposure following administration of JUVISYNC, while simvastatin AUC decreased by 24%, simvastatin Cmax increased by 20%, and simvastatin acid AUC and Cmax increased by 37% and 116%, respectively. The clinical significance of the above exposure changes in simvastatin and simvastatin acid is not known. JUVISYNC is recommended to be taken in the evening as indicated in simvastatin labeling.

Sitagliptin

The pharmacokinetics of sitagliptin has been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100 mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 to 4 hours postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100 mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half-life (t½) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin was generally similar in healthy subjects and in patients with type 2 diabetes.

The absolute bioavailability of sitagliptin is approximately 87%.

Simvastatin

Simvastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid (simvastatin acid), a potent inhibitor of HMG-CoA reductase.

Peak plasma concentrations of simvastatin lactone and simvastatin acid were attained within 1.5 and 4-6 hours postdose, respectively. For simvastatin no substantial deviation from linearity of AUC of inhibitors in the general circulation was observed at doses up to 120 mg.

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%).

Simvastatin

Both simvastatin and its β-hydroxyacid metabolite are highly bound (approximately 95%) to human plasma proteins. Rat studies indicate that when radiolabeled simvastatin was administered, simvastatin­derived radioactivity crossed the blood-brain barrier.

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.

Simvastatin

The major active metabolites of simvastatin present in human plasma are the β-hydroxyacid of simvastatin and its 6'-hydroxy, 6'-hydroxymethyl, and 6'-exomethylene derivatives. Since simvastatin undergoes extensive first-pass extraction in the liver, the availability of the drug to the general circulation is low ( < 5%).

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 t½ 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.

Simvastatin

Following an oral dose of 14C-labeled simvastatin in man, 13% of the dose was excreted in urine and 60% in feces. Plasma concentrations of total radioactivity (simvastatin plus 14C-metabolites) peaked at 4 hours and declined rapidly to about 10% of peak by 12 hours postdose.

Special Populations

Renal Impairment

Sitagliptin

A single-dose, open-label study was conducted to evaluate the pharmacokinetics of sitagliptin (50 mg dose) in patients with varying degrees of chronic renal impairment compared to normal healthy control subjects. The study included patients with renal impairment classified on the basis of creatinine clearance as mild (50 to < 80 mL/min), moderate (30 to < 50 mL/min), and severe ( < 30 mL/min), as well as patients with ESRD on hemodialysis. In addition, the effects of renal impairment on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal impairment were assessed using population pharmacokinetic analyses. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula:

Males: (weight in kg) x (140 – age)
(72) x serum creatinine (mg/100 mL)
Females (0.85) x (above value)

Compared to normal healthy control subjects, an approximate 1.1-to 1.6-fold increase in plasma AUC of sitagliptin was observed in patients with mild renal impairment. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal impairment is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal impairment and in patients with severe renal impairment, including patients with ESRD on hemodialysis, respectively. To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, a lower dosage is recommended in patients with moderate renal impairment. JUVISYNC should not be used in patients with severe renal impairment. [See DOSAGE AND ADMINISTRATION; 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). 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.

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.

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.

Simvastatin

In a study including 16 elderly patients between 70 and 78 years of age who received simvastatin 40 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age [see WARNINGS AND PRECAUTIONS; Use In Specific Populations].

Pediatric

Sitagliptin

Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.

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.

Drug Interactions

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

Effects of Coadministered Sitagliptin and Simvastatin on Other Drugs

Digoxin: There was an increase in the area under the curve (AUC, 26%) and mean peak drug concentration (Cmax, 41%) of digoxin with the coadministration of 100 mg sitagliptin and 80 mg simvastatin for 5 days. Patients receiving digoxin and JUVISYNC should be monitored.

Effects of Sitagliptin on Other Drugs

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Metformin: Coadministration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.

Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.

Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that sitagliptin is not an inhibitor of CYP2C8-mediated metabolism.

Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Oral Contraceptives: Coadministration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

Effects of Other Drugs on Sitagliptin

Clinical data described below suggest that sitagliptin is not susceptible to clinically meaningful interactions by coadministered medications.

Metformin: Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.

Cyclosporine: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100 mg oral dose of sitagliptin and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.

Effects of Simvastatin on Other Drugs

CYP3A4 Inhibitors: In a study of 12 healthy volunteers, simvastatin at the 80 mg dose had no effect on the metabolism of the probe cytochrome P450 isoform 3A4 (CYP3A4) substrates midazolam and erythromycin. This indicates that simvastatin is not an inhibitor of CYP3A4, and, therefore, is not expected to affect the plasma levels of other drugs metabolized by CYP3A4. Effects of Other Drugs on Simvastatin

Cyclosporine: Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of statins. The increase in AUC for simvastatin acid is presumably due, in part, to inhibition of CYP3A4.

CYP3A4 Inhibitors: The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS].

Table 6: Effect of Coadministered Drugs or Grapefruit Juice on Simvastatin Systemic Exposure

Coadministered Drug or Grapefruit Juice Dosing of Coadministered Drug or Grapefruit Juice Dosing of Simvastatin Geometric Mean Ratio (Ratio* with / without coadministered drug) No Effect = 1.00
  AUC Cmax
Contraindicated with JUVISYNC [see CONTRAINDICATIONS; WARNINGS AND PRECAUTIONS]
Telithromycin† 200 mg QD for 4 days 80 mg simvastatin acid‡ 12 15
simvastatin 8.9 5.3
Nelfinavir† 1250 mg BID for 14 days 20 mg QD for 28 days simvastatin acid‡
simvastatin 6 6.2
Itraconazole† 200 mg QD for 4 days 80 mg simvastatin acid‡ 13.1
simvastatin 13.1
Posaconazole 100 mg (oral suspension) QD for 13 days 200 mg (oral suspension) QD for 13 days 40 mg simvastatin acid 7.3 9.2
simvastatin 10.3 9.4
40 mg simvastatin acid 8.5 9.5
simvastatin 10.6 11.4
Gemfibrozil 600 mg BID for 3 days 40 mg simvastatin acid 2.85 2.18
simvastatin 1.35 0.91
Avoid grapefruit juice [see WARNINGS AND PRECAUTIONS]
Grapefruit Juice§ (high dose) 200 mL of double-strength TID¶ 60 mg single dose simvastatin acid 7
simvastatin 16
Grapefruit Juice§ (low dose) 8 oz (about 237 mL) of single-strength# 20 mg single dose simvastatin acid 1.3
simvastatin 1.9
Avoid taking with > 10 mg simvastatin (100 mg/10 mg or 50 mg/10 mg JUVISYNC), based on clinical and/or postmarketing experience [see WARNINGS AND PRECAUTIONS]
Verapamil SR 240 mg QD Days 1-7 then 240 mg BID on Days 8-10 80 mg on Day 10 simvastatin acid 2.3 2.4
simvastatin 2.5 2.1
Diltiazem 120 mg BID for 10 days 80 mg on Day 10 simvastatin acid 2.69 2.69
simvastatin 3.10 2.88
Diltiazem 120 mg BID for 14 days 20 mg on Day 14 simvastatin 4.6 3.6
Dronedarone 400 mg BID for 14 days 40 mg QD for 14 days simvastatin acid 1.96 2.14
simvastatin 3.90 3.75
Avoid taking with > 20 mg simvastatin (100 mg/20 mg or 50 mg/20 mg JUVISYNC), based on clinical and/or postmarketing experience [see WARNINGS AND PRECAUTIONS]
Amlodipine 10 mg QD for 10 days 80 mg on Day 10 simvastatin acid 1.58 1.56
simvastatin 1.77 1.47
Ranolazine SR 1000 mg BID for 7 days 80 mg on Day 1 and Days 6-9 simvastatin acid 2.26 2.28
simvastatin 1.86 1.75
Amiodarone 400 mg QD for 3 days 40 mg on Day 3 simvastatin acid 1.75 1.72
simvastatin 1.76 1.79
Avoid taking with >20 mg simvastatin (or 40 mg for patients who have previously taken 80 mg simvastatin chronically, e.g., for 12 months or more, without evidence of muscle toxicity), based on clinical experience
Lomitapide 60 mg QD for 7 days 40 mg single dose simvastatin acid 1.7 1.6
simvastatin 2 2
Lomitapide 10 mg QD for 7 days 20 mg single dose simvastatin acid 1.4 1.4
simvastatin 1.6 1.7
No dosing adjustmments required for the following:
Fenofibrate 160 mg QD for 14 days 80 mg QD on Days 8-14 simvastatin acid 0.64 0.89
simvastatin 0.89 0.83
Niacin extended-release Þ 2 g single dose 20 mg single dose simvastatin acid 1.6 1.84
simvastatin 1.4 1.08
Propranolol 80 mg single dose 80 mg single dose total inhibitor 0.79 ↓from 33.6 to 21.1 ng•eq/mL
active inhibitor 0.79 ↓from 7.0 to 4.7 ng•eq/mL
* Results based on a chemical assay except results with propranolol as indicated.
† Results could be representative of the following CYP3A4 inhibitors: ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, and nefazodone.
‡ Simvastatin acid refers to the β-hydroxyacid of simvastatin.
§ The effect of amounts of grapefruit juice between those used in these two studies on simvastatin pharmacokinetics has not been studied.
¶ Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose simvastatin and 30 and 90 minutes following single dose simvastatin on Day 3.
# Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and simvastatin was administered in the evening on Day 3.
Þ Chinese patients have an increased risk for myopathy with simvastatin coadministered with lipid-modifying doses ( ≥ 1 gram/day niacin) of niacin-containing products, and the risk is dose-related [see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS].

Animal Toxicology And/Or Pharmacology

Simvastatin

Optic nerve degeneration was seen in clinically normal dogs treated with simvastatin for 14 weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 24 times higher than the mean plasma drug level in humans taking 40 mg/day.

A chemically similar drug in this class also produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean plasma drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.

CNS vascular lesions, characterized by perivascular hemorrhage and edema, mononuclear cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small vessels were seen in dogs treated with simvastatin at a dose of 360 mg/kg/day, a dose that produced mean plasma drug levels that were about 28 times higher than the mean plasma drug levels in humans taking 40 mg/day. Similar CNS vascular lesions have been observed with several other drugs of this class.

There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day (44 and 50 times the human AUC at 40 mg/day, respectively) and in dogs after three months at 90 mg/kg/day (38 times) and at two years at 50 mg/kg/day (10 times).

Clinical Studies

Sitagliptin Clinical Studies

There were approximately 5200 patients with type 2 diabetes randomized in nine double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of sitagliptin on glycemic control. In a pooled analysis of seven of these studies, the ethnic/racial distribution was approximately 59% white, 20% Hispanic, 10% Asian, 6% black, and 6% other groups. Patients had an overall mean age of approximately 55 years (range 18 to 87 years). In addition, an active (glipizide)­controlled study of 52 weeks duration was conducted in 1172 patients with type 2 diabetes who had inadequate glycemic control on metformin.

In patients with type 2 diabetes, treatment with sitagliptin produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.

Monotherapy

A total of 1262 patients with type 2 diabetes participated in two double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of sitagliptin monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent, and underwent a diet, exercise, and drug washout period of about 7 weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized after completing a 2-week single-blind placebo run-in period; patients not currently on antihyperglycemic agents (off therapy for at least 8 weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week single-blind placebo run-in period. In the 18-week study, 521 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg, and in the 24-week study 741 patients were randomized to placebo, sitagliptin 100 mg, or sitagliptin 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or sitagliptin.

Treatment with sitagliptin at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 7). In the 18-week study, 9% of patients receiving sitagliptin 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving sitagliptin 100 mg and 21% of patients receiving placebo required rescue therapy. The improvement in A1C compared to placebo was not affected by gender, age, race, prior antihyperglycemic therapy, or baseline BMI. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with sitagliptin appears to be related to the degree of A1C elevation at baseline. In these 18-and 24-week studies, among patients who were not on an antihyperglycemic agent at study entry, the reductions from baseline in A1C were -0.7% and -0.8%, respectively, for those given sitagliptin, and -0.1% and -0.2%, respectively, for those given placebo. Overall, the 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose. Body weight did not increase from baseline with sitagliptin therapy in either study, compared to a small reduction in patients given placebo.

Table 7: Glycemic Parameters in 18-and 24-Week Placebo-Controlled Studies of Sitagliptin in Patients with Type 2 Diabetes*

  18-Week Study 24-Week Study
Sitagliptin 100 mg Placebo Sitagliptin 100 mg Placebo
A1C (%) N = 193 N = 103 N = 229 N = 244
  Baseline (mean) 8 8.1 8 8
  Change from baseline (adjusted mean†) -0.5 0.1 -0.6 0.2
  Difference from placebo (adjusted mean†) (95% CI) -0.6‡ (-0.8, -0.4) -0.8‡ (-1.0, -0.6)
  Patients (%) achieving A1C < 7% 69 (36%) 16 (16%) 93 (41%) 41 (17%)
FPG (mg/dL) N = 201 N = 107 N = 234 N = 247
  Baseline (mean) 180 184 170 176
  Change from baseline (adjusted mean†) -13 7 -12 5
  Difference from placebo (adjusted mean†) (95% CI) -20‡ (-31, -9) -17‡ (-24, -10)
2-hour PPG (mg/dL) § § N = 201 N = 204
  Baseline (mean)     257 271
  Change from baseline (adjusted mean†)     -49 -2
  Difference from placebo (adjusted mean†) (95% CI)     -47‡ (-59, -34)
* Intent-to-treat population using last observation on study prior to metformin rescue therapy.
† Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡ p < 0.001 compared to placebo.
§ Data not available.

Add-on Combination Therapy with Metformin

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. Patients already on metformin (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 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 (at a dose of at least 1500 mg per day) in monotherapy. Patients with inadequate glycemic control (A1C 7% to 10%) 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, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 8). 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 8: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Add-on Combination Therapy with Metformin*

  Sitagliptin 100 mg + Metformin Placebo + Metformin
A1C (%) N = 453 N = 224
  Baseline (mean) 8 8
  Change from baseline (adjusted mean†) -0.7 0
  Difference from placebo + metformin (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 (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 (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.

Initial Combination Therapy with Metformin

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 as initial therapy in combination with metformin. Patients on an antihyperglycemic agent (N=541) discontinued the agent, and 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 initial therapy with placebo, 100 mg of sitagliptin once daily, 500 mg or 1000 mg of metformin twice daily, or 50 mg of sitagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with glyburide (glibenclamide) rescue.

Initial therapy with the combination of sitagliptin and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to sitagliptin alone (Table 9, Figure 1). Mean reductions from baseline in A1C were generally greater for patients with higher baseline A1C values. 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 500 mg bid, -1.1%; metformin 1000 mg bid, -1.2%; sitagliptin 50 mg bid with metformin 500 mg bid, -1.6%; sitagliptin 50 mg bid with metformin 1000 mg bid, -1.9%; and for patients receiving placebo, -0.2%. The decrease in body weight in the groups given sitagliptin in combination with metformin was similar to that in the groups given metformin alone or placebo.

Table 9: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy*

  Placebo Sitagliptin 100 mg QD Metformin 500 mg bid Metformin 1000 mg bid Sitagliptin 50 mg bid + Metformin 500 mg bid Sitagliptin 50 mg bid + Metformin 1000 mg bid
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, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes*

Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin, Alone and in Combination as Initial Therapy in Patients with Type 2 Diabetes - Illustration

* All Patients Treated Population; least squares means adjusted for prior antihyperglycemic therapy and baseline value.

Initial combination therapy or maintenance of combination therapy may not be appropriate for all patients. These management options are left to the discretion of the health care provider.

Active-Controlled Study vs Glipizide in Combination with Metformin

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 monotherapy (dose of ≥ 1500 mg per day) which included washout of medications other than metformin, 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 10). 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 10: Glycemic Parameters in a 52-Week Study Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*

  Sitagliptin 100 mg Glipizide
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 (Per Protocol Population)*

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 - Illustration

* The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52.

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).

Add-on Combination Therapy with Pioglitazone

A total of 353 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 pioglitazone. Patients on any oral antihyperglycemic agent in monotherapy (N=212) or on a PPARγ agent in combination therapy (N=106) or not on an antihyperglycemic agent (off therapy for at least 8 weeks, N=34) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients with inadequate glycemic control (A1C 7% to 10%) 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 metformin rescue. Glycemic endpoints measured were A1C and fasting glucose.

In combination with pioglitazone, sitagliptin provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 11). Rescue therapy was used in 7% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change.

Table 11: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Add-on Combination Therapy with Pioglitazone*

  Sitagliptin 100 mg + Pioglitazone Placebo + Pioglitazone
A1C (%) N = 163 N = 174
  Baseline (mean) 8.1 8
  Change from baseline (adjusted mean†) -0.9 -0.2
  Difference from placebo + pioglitazone (adjusted mean†) (95% CI) -0.7‡ (-0.9, -0.5)  
  Patients (%) achieving A1C < 7% 74 (45%) 40 (23%)
FPG (mg/dL) N = 163 N = 174
  Baseline (mean) 168 166
  Change from baseline (adjusted mean†) -17 1
  Difference from placebo + pioglitazone (adjusted mean†) (95% CI) -18‡ (-24, -11)  
* Intent-to-treat population using last observation on study prior to metformin rescue therapy.
† Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡ p < 0.001 compared to placebo + pioglitazone.

Initial Combination Therapy with Pioglitazone

A total of 520 patients with type 2 diabetes and inadequate glycemic control on diet and exercise participated in a 24-week, randomized, double-blind study designed to assess the efficacy of sitagliptin as initial therapy in combination with pioglitazone. Patients not on antihyperglycemic agents at study entry ( < 4 weeks cumulative therapy over the past 2 years, and with no treatment over the prior 4 months) with inadequate glycemic control (A1C 8% to 12%) immediately entered the 2-week single-blind placebo run-in period and then were randomized. Approximately equal numbers of patients were randomized to receive initial therapy with 100 mg of sitagliptin in combination with 30 mg of pioglitazone once daily or 30 mg of pioglitazone once daily as monotherapy. There was no glycemic rescue therapy in this study.

Initial therapy with the combination of sitagliptin and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 12). The improvement in A1C was generally consistent across subgroups defined by gender, age, race, baseline BMI, baseline A1C, or duration of disease. In this study, patients treated with sitagliptin in combination with pioglitazone had a mean increase in body weight of 1.1 kg compared to pioglitazone alone (3.0 kg vs. 1.9 kg).

Table 12: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin in Combination with Pioglitazone as Initial Therapy*

  Sitagliptin 100 mg + Pioglitazone Pioglitazone
A1C (%) N = 251 N = 246
  Baseline (mean) 9.5 9.4
  Change from baseline (adjusted mean†) -2.4 -1.5
  Difference from pioglitazone (adjusted mean†) (95% CI) -0.9‡ (-1.1, -0.7)
  Patients (%) achieving A1C < 7% 151 (60%) 68 (28%)
FPG (mg/dL) N = 256 N = 253
  Baseline (mean) 203 201
  Change from baseline (adjusted mean†) -63 -40
  Difference from pioglitazone (adjusted mean†) (95% CI) -23‡ (-30, -15)
2-hour PPG (mg/dL) N = 216 N = 211
  Baseline (mean) 283 284
  Change from baseline (adjusted mean†) -114 -69
  Difference from pioglitazone (adjusted mean†) (95% CI) -45‡ (-57, -32)
* Intent-to-treat population using last observation on study.
† Least squares means adjusted for baseline value.
‡ p < 0.001 compared to placebo + pioglitazone.

Add-on Combination Therapy with Metformin 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 and rosiglitazone. Patients on dual therapy with metformin ≥ 1500 mg/day and rosiglitazone ≥ 4 mg/day or with metformin ≥ 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 ≥ 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 study were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was W eek 18.

In combination with metformin and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 13) at W eek 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 13: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin and Rosiglitazone*

  Sitagliptin 100 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone
A1C (%) N = 176 N = 93
  Baseline (mean) 8.8 8.7
  Change from baseline (adjusted mean†) -1 -0.4
  Difference from placebo + rosiglitazone + metformin (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 (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 (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.

Add-on Combination Therapy with Glimepiride, with or without Metformin

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. Patients entered a run-in treatment period on glimepiride ( ≥ 4 mg per day) alone or glimepiride in combination with metformin ( ≥ 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.

In combination with glimepiride, with or without metformin, sitagliptin provided significant improvements in A1C and FPG compared to placebo (Table 14). In the entire study population (patients on sitagliptin in combination with glimepiride and patients on sitagliptin in combination with glimepiride and metformin), a mean reduction from baseline relative to placebo in A1C of -0.7% and in FPG of -20 mg/dL was seen. Rescue therapy was used in 12% of patients treated with sitagliptin 100 mg and 27% of patients treated with placebo. In this study, patients treated with sitagliptin had a mean increase in body weight of 1.1 kg vs. placebo (+0.8 kg vs. -0.4 kg). In addition, there was an increased rate of hypoglycemia. [See WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

Table 14: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-On Combination Therapy with Glimepiride, with or without Metformin*

  Sitagliptin 100 mg + Glimepiride Placebo + Glimepiride Sitagliptin 100 mg + Glimepiride + Metformin Placebo + Glimepiride + Metformin
A1C (%) N = 102 N = 103 N = 115 N = 105
  Baseline (mean) 8.4 8.5 8.3 8.3
  Change from baseline (adjusted mean†) -0.3 0.3 -0.6 0.3
  Difference from placebo (adjusted mean†) (95% CI) -0.6‡ (-0.8, -0.3) -0.9‡ (-1.1, -0.7)
  Patients (%) achieving A1C < 7% 11 (11%) 9 (9%) 26 (23%) 1 (1%)
FPG (mg/dL) N = 104 N = 104 N = 115 N = 109
  Baseline (mean) 183 185 179 179
  Change from baseline (adjusted mean†)   -1 18 -8 13
  Difference from placebo (adjusted mean†) (95% CI) -19§ (-32, -7) -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.
§ p < 0.01 compared to placebo.

Add-on Combination Therapy with Insulin (with or without Metformin)

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 (with or without metformin). The racial distribution in this study was approximately 70% white, 18% Asian, 7% black, and 5% other groups. Approximately 14% of the patients in this study were Hispanic. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin ( ≥ 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 or placebo, 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.

The median daily insulin dose at baseline was 42 units in the patients treated with sitagliptin and 45 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. In combination with insulin (with or without metformin), sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 15). Both treatment groups had an adjusted mean increase in body weight of 0.1 kg from baseline to Week 24. There was an increased rate of hypoglycemia in patients treated with sitagliptin. [See WARNINGS AND PRECAUTIONS; ADVERSE REACTIONS]

Table 15: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin as Add-on Combination Therapy with Insulin*

  Sitagliptin 100 mg + Insulin (+/-Metformin) Placebo + Insulin (+/-Metformin)
A1C (%) N = 305 N = 312
  Baseline (mean) 8.7 8.6
  Change from baseline (adjusted mean†) -0.6 -0.1
  Difference from placebo (adjusted mean†,‡) (95% CI) -0.6§ (-0.7, -0.4)
  Patients (%) achieving A1C < 7% 39 (12.8%) 16 (5.1%)
FPG (mg/dL) N = 310 N = 313
  Baseline (mean) 176 179
  Change from baseline (adjusted mean†) -18 -4
  Difference from placebo (adjusted mean†) (95% CI) -15§ (-23, -7)
2-hour PPG (mg/dL) N = 240 N = 257
  Baseline (mean) 291 292
  Change from baseline (adjusted mean†) -31 5
  Difference from placebo (adjusted mean†) (95% CI) -36§ (-47, -25)
* Intent-to-treat population using last observation on study prior to rescue therapy.
† Least squares means adjusted for metformin use at the screening visit (yes/no), type of insulin used at the screening visit (pre-mixed vs. non-pre-mixed [intermediate-or long-acting]), and baseline value.
‡ Treatment by stratum interaction was not significant (p > 0.10) for metformin stratum and for insulin stratum.
§ p < 0.001 compared to placebo.

Simvastatin Clinical Studies

Reductions in Risk of CHD Mortality and Cardiovascular Events

In 4S, the effect of therapy with simvastatin on total mortality was assessed in 4444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, patients were treated with standard care, including diet, and either simvastatin 20-40 mg/day (n=2221) or placebo (n=2223) for a median duration of 5.4 years. Over the course of the study, treatment with simvastatin led to mean reductions in total-C, LDL-C and TG of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. Simvastatin significantly reduced the risk of mortality by 30% (p=0.0003, 182 deaths in the simvastatin group vs 256 deaths in the placebo group). The risk of CHD mortality was significantly reduced by 42% (p=0.00001, 111 vs 189 deaths). There was no statistically significant difference between groups in non-cardiovascular mortality. Simvastatin significantly decreased the risk of having major coronary events (CHD mortality plus hospital-verified and silent non-fatal myocardial infarction [MI]) by 34% (p < 0.00001, 431 vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. Simvastatin significantly reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37% (p < 0.00001, 252 vs 383 patients). Simvastatin significantly reduced the risk of fatal plus non-fatal cerebrovascular events (combined stroke and transient ischemic attacks) by 28% (p=0.033, 75 vs 102 patients). Simvastatin reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL cholesterol levels. Because there were only 53 female deaths, the effect of simvastatin on mortality in women could not be adequately assessed. However, simvastatin significantly lessened the risk of having major coronary events by 34% (60 vs 91 women with one or more event). The randomization was stratified by angina alone (21% of each treatment group) or a previous MI. Because there were only 57 deaths among the patients with angina alone at baseline, the effect of simvastatin on mortality in this subgroup could not be adequately assessed. However, trends in reduced coronary mortality, major coronary events and revascularization procedures were consistent between this group and the total study cohort. Additionally, simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in elderly patients ( ≥ 65 years), compared with younger patients.

The Heart Protection Study (HPS) was a large, multi-center, placebo-controlled, double-blind study with a mean duration of 5 years conducted in 20,536 patients (10,269 on simvastatin 40 mg and 10,267 on placebo), including 5963 patients with diabetes mellitus (2978 on simvastatin and 2985 on placebo). Patients were allocated to treatment using a covariate adaptive method which took into account the distribution of 10 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients had a mean age of 64 years (range 40­80 years), were 97% Caucasian and were at high risk of developing a major coronary event because of existing CHD (65%), diabetes (Type 2, 26%; Type 1, 3%), history of stroke or other cerebrovascular disease (16%), peripheral vessel disease (33%), or hypertension in males ≥ 65 years (6%). At baseline, 3421 patients (17%) had LDL-C levels below 100 mg/dL, of whom 953 (5%) had LDL-C levels below 80 mg/dL; 7068 patients (34%) had levels between 100 and 130 mg/dL; and 10,047 patients (49%) had levels greater than 130 mg/dL.

The HPS results showed that simvastatin 40 mg/day significantly reduced: total and CHD mortality; non-fatal MI, stroke, and revascularization procedures (coronary and non-coronary) (see Table 16).

Table 16: Summary of Heart Protection Study Results

Endpoint Simvastatin
(N=10,269)
n (%)*
Placebo
(N=10,267)
n (%)*
Risk Reduction (%) (95% CI) p-Value
Primary
Mortality 1328 (12.9) 1507 (14.7) 13 (6-19) p=0.0003
CHD mortality 587 (5.7) 707 (6.9) 18 (8-26) p=0.0005
Secondary
Non-fatal 357 (3.5) 574 (5.6) 38 (30-46) p < 0.0001
MI Stroke 444 (4.3) 585 (5.7) 25 (15-34) p < 0.0001
Tertiary
Coronary revascularization 513 (5) 725 (7.1) 30 (22-38) p < 0.0001
Peripheral and other non-coronary revascularization 450 (4.4) 532 (5.2) 16 (5-26) p=0.006
* n = number of patients with indicated event

Two composite endpoints were defined in order to have sufficient events to assess relative risk reductions across a range of baseline characteristics (see Figure 3). A composite of major coronary events (MCE) was comprised of CHD mortality and non-fatal MI (analyzed by time-to-first event; 898 patients treated with simvastatin had events and 1212 patients on placebo had events). A composite of major vascular events (MVE) was comprised of MCE, stroke and revascularization procedures including coronary, peripheral and other non-coronary procedures (analyzed by time-to-first event; 2033 patients treated with simvastatin had events and 2585 patients on placebo had events). Significant relative risk reductions were observed for both composite endpoints (27% for MCE and 24% for MVE, p < 0.0001). Treatment with simvastatin produced significant relative risk reductions for all components of the composite endpoints. The risk reductions produced by simvastatin in both MCE and MVE were evident and consistent regardless of cardiovascular disease related medical history at study entry (i.e., CHD alone; or peripheral vascular disease, cerebrovascular disease, diabetes or treated hypertension, with or without CHD), gender, age, creatinine levels up to the entry limit of 2.3 mg/dL, baseline levels of LDL-C, HDL-C, apolipoprotein B and A-1, baseline concomitant cardiovascular medications (i.e., aspirin, beta blockers, or calcium channel blockers), smoking status, alcohol intake, or obesity. Diabetic patients showed risk reductions for MCE and MVE (27% and 22%, respectively; p < 0.0001) due to simvastatin treatment regardless of baseline A1C levels or obesity with the greatest effects seen for diabetic patients without CHD.

Figure 3: The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS

The Effects of Treatment with Simvastatin on Major Vascular Events and Major Coronary Events in HPS - Illustration

N = number of patients in each subgroup. The inverted triangles are point estimates of the relative risk, with their 95% confidence intervals represented as a line. The area of a triangle is proportional to the number of patients with MVE or MCE in the subgroup relative to the number with MVE or MCE, respectively, in the entire study population. The vertical solid line represents a relative risk of one. The vertical dashed line represents the point estimate of relative risk in the entire study population.

Modifications of Lipid Profiles

Primary Hyperlipidemia (Fredrickson type lla and llb)

Simvastatin has been shown to be effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of hyperlipidemia and in mixed hyperlipidemia. Maximal to near maximal response is generally achieved within 4-6 weeks and maintained during chronic therapy. Simvastatin consistently and significantly decreased total-C, LDL-C, total-C/HDL-C ratio, and LDL-C/HDL-C ratio; simvastatin also decreased TG and increased HDL-C (see Table 17).

Table 17: Mean Response in Patients with Primary Hyperlipidemia and Combined (mixed) Hyperlipidemia (Mean Percent Change from Baseline After 6 to 24 Weeks)

TREATMENT N TOTAL-C LDL-C HDL-C TG*
Lower Dose Comparative Study† (Mean % Change at Week 6)
  Simvastatin 5 mg q.p.m. 109 -19 -26 10 -12
  Simvastatin 10 mg q.p.m. 110 -23 -30 12 -15
Scandinavian Simvastatin Survival Study‡ (Mean % Change at Week 6) 
  Placebo 2223 -1 -1 0 -2
  Simvastatin 20 mg q.p.m. 2221 -28 -38 8 -19
Upper Dose Comparative Study§,¶ (Mean % Change Averaged at Weeks 18 and 24)
  Simvastatin 40 mg q.p.m. 433 -31 -41 9 -18
Multi-Center Combined Hyperlipidemia Study# (Mean % Change at Week 6)
  Placebo 125 1 2 3 -4
  Simvastatin 40 mg q.p.m. 123 -25 -29 13 -28
* median percent change
† mean baseline LDL-C 244 mg/dL and median baseline TG 168 mg/dL
‡ mean baseline LDL-C 188 mg/dL and median baseline TG 128 mg/dL
§ mean baseline LDL-C 226 mg/dL and median baseline TG 156 mg/dL
¶ Study also included another treatment arm receiving a different dose of simvastatin; baseline mean LDL-C and median TG values were calculated across all treatment arms in study
# mean baseline LDL-C 156 mg/dL and median baseline TG 391 mg/dL.

Hypertriglyceridemia (Fredrickson type lV)

The results of a subgroup analysis in 74 patients with type lV hyperlipidemia from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 18.

Table 18: Six-Week, Lipid-Lowering Effects of Simvastatin in Type lV Hyperlipidemia Median Percent Change (25th and 75th percentile) from Baseline*

TREATMENT N Total-C LDL-C HDL-C TG VLDL-C Non-HDL-C
Placebo 74 +2 (-7, +7) +1 (-8, +14) +3 (-3, +10) -9 (-25, +13) -7 (-25, +11) +1 (-9, +8)
Simvastatin 40 mg/day 74 -25 (-34, -19) -28 (-40, -17) +11 (+5, +23) -29 (-43, -16) -37 (-54, -23) -32 (-42, -23)
* The median baseline values (mg/dL) for the patients in this study were: total-C = 254, LDL-C = 135, HDL-C = 36, TG = 404, VLDL-C = 83, and non-HDL-C = 215.

Dysbetalipoproteinemia (Fredrickson type lll)

The results of a subgroup analysis in 7 patients with type lll hyperlipidemia (dysbetalipoproteinemia) (apo E2/2) (VLDL-C/TG > 0.25) from a 130-patient, double-blind, placebo-controlled, 3-period crossover study are presented in Table 19.

Table 19: Six-Week, Lipid-Lowering Effects of Simvastatin in Type lll Hyperlipidemia Median Percent Change (min, max) from Baseline*

TREATMENT N Total-C LDL-C + IDL HDL-C TG VLDL-C +IDL Non-HDL-C
Placebo 7 -8(-24, +34) -8(-27, +23) -2(-21, +16) 4(-22, +90) -4(-28, +78) -8(-26, -39)
Simvastatin 40 mg/day 7 -50(-66, -39) -50(-60, -31) 7(-8, +23) -41(-74, -16) -58(-90, -37) -57(-72, -44)
* The median baseline values (mg/dL) were: total-C = 324, LDL-C = 121, HDL-C = 31, TG = 411, VLDL-C = 170, and non-HDL-C = 291.

Homozygous Familial Hypercholesterolemia

In a controlled clinical study, 4 patients, 19-27 years of age, with homozygous familial hypercholesterolemia received simvastatin 40 mg/day in a single dose or in 3 divided doses. Reductions in LDL-C were observed for all patients. The mean LDL-C reduction for the 40 mg dose was 14% (range 8% to 23%, median 12%).

Endocrine Function

In clinical studies, simvastatin did not impair adrenal reserve or significantly reduce basal plasma cortisol concentration. Small reductions from baseline in basal plasma testosterone in men were observed in clinical studies with simvastatin, an effect also observed with other statins and the bile acid sequestrant cholestyramine. There was no effect on plasma gonadotropin levels. In a placebo-controlled, 12-week study there was no significant effect of simvastatin 80 mg on the plasma testosterone response to human chorionic gonadotropin. In another 24-week study, simvastatin 20-40 mg had no detectable effect on spermatogenesis. In 4S, in which 4444 patients were randomized to simvastatin 20-40 mg/day or placebo for a median duration of 5.4 years, the incidence of male sexual adverse events in the two treatment groups was not significantly different. Because of these factors, the small changes in plasma testosterone are unlikely to be clinically significant. The effects, if any, on the pituitary-gonadal axis in pre-menopausal women are unknown.

Last reviewed on RxList: 3/11/2014
This monograph has been modified to include the generic and brand name in many instances.

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