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磷酸西他列汀片|JANUVIA(sitagliptin Tablets)

2013-12-06 08:18:10  作者:新特药房  来源:互联网  浏览次数:418  文字大小:【】【】【
简介:默沙东生产的Januvia属于二肽基肽酶-4(DPP-4)抑制剂类药物,是第一种通过提高自身肌体能力控制血糖水平的新型治疗2型糖尿病药物。根据审批结果,JANUVIA可用作单一治疗药物,也可用作其它两种口服降糖药(二甲双 ...

磷酸西他列汀片, 是一种新型降糖药二肽基肽酶-4 (DPP-4)抑制剂, 可提高人体自身降低过高血糖水平的能力。
Januvia是DPP-4抑制剂类药物中首种获批准的药物。磷酸西他列汀作用特点是在刺激胰岛素分泌的同时,能减轻饥饿感,而且不会使体重增加,也不会发生低血糖和水肿现象,适合血糖控制不好且经常发生低血糖的糖尿病患者使用。
经临床552例轻中度2型糖尿病患者验证,每天服一次磷酸西他列汀,每次服100毫克,服药12周后可使糖化血红蛋白降低0.6%-1.1%。
2006年10月17日,美国FDA批准Januvia用于2型糖尿病患者的新型口服降糖药,该药显示出更少的副反应。这使得糖尿病患者获得一种控制血糖的新方式。
据美国FDA介绍:新批准的由美国默克公司制造的口服降糖药Januvia,能够提高患者自身控制血糖的能力,该药的临床研究显示其副作用比以往的口服降糖药少。
FDA批准在饮食控制和增强锻炼的基础上应用Januvia来提高对2型糖尿病患者血糖的控制。Januvia可单独,也可与其他口服降糖药联合使用。
Januvia的降糖机制不同于以往的降糖药。Januvia能够提高一种激素的水平,该激素能促使胰岛细胞产生胰岛素,并同时促使肝脏停止释放葡萄糖。二肽基酶IV(DPP-IV)是该激素的灭活酶,而Januvia即通过抑止二肽基酶IV的作用而使该激素灭活减少,从而起到刺激胰岛素产生的作用。
美国FDA药品评价与研究中心主任Steven Galson博士介绍:“对于数百万血糖控制不佳的2型糖尿病患者来说,Januvia的批准给他们带来了希望,我们从此有了一个全新的控制血糖的药物。”
美国糖尿病协会的专家称糖尿病患者需要把糖化血红蛋白的水平控制在7%以下,这样能够减少许多并发症的发生,如肾功能衰竭和糖尿病足。在6月份的糖尿病会议上,默克公司称Januvia在一年内能使血糖水平降低0.67%,与格列吡嗪的作用相当。大约2/3的患者能将血红蛋白控制在7%以下。


HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use JANUVIA safely and effectively. See full prescribing information for JANUVIA.
JANUVIA ® (sitagliptin) Tablets
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
Warnings and Precautions
Severe and Disabling Arthralgia (5.5) 08/2015
INDICATIONS AND USAGE
JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. (1.1)
Important Limitations of Use:
JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. (1.2)
JANUVIA has not been studied in patients with a history of pancreatitis. (1.2, 5.1)
DOSAGE AND ADMINISTRATION
The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food. (2.1)
Dosage adjustment is recommended for patients with moderate or severe renal insufficiency or end-stage renal disease. (2.2)

Dosage Adjustment in Patients With Moderate, Severe and End Stage Renal Disease (ESRD) (2.2)
50 mg once daily 25 mg once daily

Moderate


CrCl ≥30 to <50 mL/min

~Serum Cr levels [mg/dL]

Men: >1.7– ≤3.0;

Women: >1.5– ≤2.5

Severe and ESRD


CrCl <30 mL/min
~Serum Cr levels [mg/dL]

Men: >3.0;

Women: >2.5;

or on dialysis

DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg, 50 mg, and 25 mg (3)
CONTRAINDICATIONS
History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema (5.4, 6.2)
WARNINGS AND PRECAUTIONS
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA. (5.1)
There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD. Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. (2.2, 5.2, 6.2)
There is an increased risk of hypoglycemia when JANUVIA is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the risk of hypoglycemia. (2.3, 5.3)
There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with JANUVIA such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUVIA, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.4, 6.2)
Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.5)
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. (5.6)
ADVERSE REACTIONS
Adverse reactions reported in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo are: upper respiratory tract infection, nasopharyngitis and headache. In the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in patients treated with JANUVIA compared to placebo. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Safety and effectiveness of JANUVIA in children under 18 years have not been established. (8.4)
There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999. (8.1)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 4/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Monotherapy and Combination Therapy
JANUVIA® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies (14).]
1.2 Important Limitations of Use
JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA. [See Warnings and Precautions (5.1).]
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosing
The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food.
2.2 Patients with Renal Insufficiency
For patients with mild renal insufficiency (creatinine clearance [CrCl] greater than or equal to 50 mL/min, approximately corresponding to serum creatinine levels of less than or equal to 1.7 mg/dL in men and less than or equal to 1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.
For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than 50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.
For patients with severe renal insufficiency (CrCl less than 30 mL/min, approximately corresponding to serum creatinine levels of greater than 3.0 mg/dL in men and greater than 2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of dialysis.
Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. [See Clinical Pharmacology (12.3).] There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.
2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia. [See Warnings and Precautions (5.3).] 
3 DOSAGE FORMS AND STRENGTHS
100 mg tablets are beige, round, film-coated tablets with "277" on one side.
50 mg tablets are light beige, round, film-coated tablets with "112" on one side.
25 mg tablets are pink, round, film-coated tablets with "221" on one side.
4 CONTRAINDICATIONS
History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. [See Warnings and Precautions (5.4); Adverse Reactions (6.2).]
5 WARNINGS AND PRECAUTIONS
5.1 Pancreatitis
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, JANUVIA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using JANUVIA.
5.2 Renal Impairment
Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. [See Dosage and Administration (2.2); Clinical Pharmacology (12.3).] Caution should be used to ensure that the correct dose of JANUVIA is prescribed for patients with moderate (creatinine clearance ≥30 to <50 mL/min) or severe (creatinine clearance <30 mL/min) renal impairment.
There have been postmarketing reports of worsening renal function, including acute renal failure, sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency has been observed with supportive treatment and discontinuation of potentially causative agents. Consideration can be given to cautiously reinitiating JANUVIA if another etiology is deemed likely to have precipitated the acute worsening of renal function.
JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in clinical trials.
5.3 Use with Medications Known to Cause Hypoglycemia
When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and Administration (2.3).]
5.4 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]
Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with JANUVIA.
5.5 Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
5.6 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled clinical studies as both monotherapy and combination therapy with metformin, pioglitazone, or rosiglitazone and metformin, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Five placebo-controlled add-on combination therapy studies were also conducted: one with metformin; one with pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily and more commonly than in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration. Incidences of hypoglycemia are shown in Table 3.
Table 1: Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding Hypoglycemia) Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causality*

Number of Patients (%)

 

Monotherapy (18 or 24 weeks) JANUVIA 100 mg Placebo
N = 443 N = 363
  Nasopharyngitis 23 (5.2) 12 (3.3)
Combination with Pioglitazone
   (24 weeks)

JANUVIA 100 mg +

Pioglitazone

Placebo +

Pioglitazone
N = 175 N = 178
  Upper Respiratory Tract Infection 11 (6.3) 6 (3.4)
  Headache 9 (5.1) 7 (3.9)
Combination with Metformin +
  Rosiglitazone
(18 weeks)

JANUVIA 100 mg +

Metformin + Rosiglitazone

Placebo +

Metformin + Rosiglitazone
N = 181 N = 97
  Upper Respiratory Tract Infection 10 (5.5) 5 (5.2)
  Nasopharyngitis 11 (6.1) 4 (4.1)
Combination with Glimepiride
  (+/- Metformin)
(24 weeks)

JANUVIA 100 mg

+ Glimepiride

(+/- Metformin)

Placebo

+ Glimepiride

(+/- Metformin)

N = 222 N = 219
  Nasopharyngitis 14 (6.3) 10 (4.6)
  Headache 13 (5.9) 5 (2.3)
Intent-to-treat population
In the 24-week study of patients receiving JANUVIA as add-on combination therapy with metformin, there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo.
In the 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without metformin), there were no adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than in patients given placebo, except for hypoglycemia (see Table 3).
In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1), through Week 54 the adverse reactions reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%).
In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2.
Table 2: Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)*

Number of Patients (%)

 

Placebo

Sitagliptin

 (JANUVIA)
100 mg QD

Metformin

500 or 1000 mg bid

Sitagliptin

50 mg bid +

Metformin

500 or 1000 mg bid

N = 176 N = 179 N = 364† N = 372
  Upper Respiratory Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2)
  Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9)
Intent-to-treat population.
Data pooled for the patients given the lower and higher doses of metformin.
In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and more commonly than in patients given pioglitazone alone.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA.
In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). [See Warnings and Precautions (5.1).]
Hypoglycemia
In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
Table 3: Incidence and Rate of Hypoglycemia* in Placebo-Controlled Clinical Studies when JANUVIA was used as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin), Regardless of Investigator Assessment of Causality

Add-On to Glimepiride
(+/- Metformin)
(24 weeks)

JANUVIA 100 mg

+ Glimepiride

(+/- Metformin)

Placebo

+ Glimepiride

(+/- Metformin)
N = 222 N = 219
  Overall (%) 27 (12.2) 4 (1.8)
  Rate (episodes/patient-year)† 0.59 0.24
  Severe (%) 0 (0.0) 0 (0.0)
Add-On to Insulin
(+/- Metformin)
(24 weeks)

JANUVIA 100 mg

+ Insulin

(+/- Metformin)

Placebo

+ Insulin

(+/- Metformin)
N = 322 N = 319
  Overall (%) 50 (15.5) 25 (7.8)
  Rate (episodes/patient-year)† 1.06 0.51
  Severe (%)‡ 2 (0.6) 1 (0.3)
Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population.
Based on total number of events (i.e., a single patient may have had multiple events).
Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.
In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on JANUVIA and 1.0% in patients given add-on placebo.
In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in combination with metformin.
In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other studies except in the study involving coadministration with insulin.
Laboratory Tests
Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known.
6.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of JANUVIA as monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.4)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and Usage (1.2); Warnings and Precautions (5.1)]; worsening renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions (5.2)]; severe and disabling arthralgia [see Warnings and Precautions (5.5)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain; pruritus; pemphigoid.
7 DRUG INTERACTIONS
7.1 Digoxin
There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B:
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
8.3 Nursing Mothers
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
This drug is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter [see Dosage and Administration (2.2); Clinical Pharmacology (12.3)].
10 OVERDOSAGE
During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg JANUVIA, a mean effect that is not considered clinically important [see Clinical Pharmacology (12.2)]. 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 JANUVIA with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for 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 dictated 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.
11 DESCRIPTION
JANUVIA Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.
Sitagliptin phosphate monohydrate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
The empirical formula is C16H15F6N5O•H3PO4•H2O and the molecular weight is 523.32. The structural formula is:


Sitagliptin phosphate monohydrate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base and the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 JANUVIA, 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, JANUVIA 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.
12.2 Pharmacodynamics
General
In patients with type 2 diabetes, administration of JANUVIA 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, JANUVIA 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 JANUVIA 100 mg, JANUVIA 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 JANUVIA 100 mg (N=81) or JANUVIA 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.
12.3 Pharmacokinetics
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 (t1/2) 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.
Absorption
The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.
Distribution
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%).
Metabolism
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.
Excretion
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.
Special Populations
Renal Insufficiency
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of JANUVIA (50 mg dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control subjects. The study included patients with renal insufficiency 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 insufficiency on sitagliptin pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency 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:
CrCl = [140 - age (years)] x weight (kg) {x 0.85 for female patients}[72 x serum creatinine (mg/dL)]
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 insufficiency. Because increases of this magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring dialysis. [See Dosage and Administration (2.2).]
Hepatic Insufficiency
In patients with moderate hepatic insufficiency (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 JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild or moderate hepatic insufficiency.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
Body Mass Index (BMI)
No dosage adjustment is necessary based on BMI. 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
No dosage adjustment is necessary based on gender. 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
No dosage adjustment is required based solely on age. 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.
Pediatric
Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been performed.
Race
No dosage adjustment is necessary based on race. 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
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 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).
Digoxin: Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma Cmax by 18%.
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.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA 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 JANUVIA 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
A two-year carcinogenicity study was conducted in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose results in exposures approximately 60 times the human exposure at the maximum recommended daily adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and 500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, nondose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
14 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 JANUVIA produced clinically significant improvements in hemoglobin A1C, fasting plasma glucose (FPG) and 2-hour post-prandial glucose (PPG) compared to placebo.
14.1 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 JANUVIA 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, JANUVIA 100 mg, or JANUVIA 200 mg, and in the 24-week study 741 patients were randomized to placebo, JANUVIA 100 mg, or JANUVIA 200 mg. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue, added on to placebo or JANUVIA.
Treatment with JANUVIA at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 4). In the 18-week study, 9% of patients receiving JANUVIA 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving JANUVIA 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 JANUVIA 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 JANUVIA, 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. The effect of JANUVIA on lipid endpoints was similar to placebo. Body weight did not increase from baseline with JANUVIA therapy in either study, compared to a small reduction in patients given placebo.
Table 4: Glycemic Parameters in 18- and 24-Week Placebo-Controlled Studies of JANUVIA in Patients with Type 2 Diabetes*

18-Week Study 24-Week Study
JANUVIA 100 mg Placebo JANUVIA 100 mg Placebo
A1C (%) N = 193 N = 103 N = 229 N = 244
  Baseline (mean) 8.0 8.1 8.0 8.0
  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.
Additional Monotherapy Study
A multinational, randomized, double-blind, placebo-controlled study was also conducted to assess the safety and tolerability of JANUVIA in 91 patients with type 2 diabetes and chronic renal insufficiency (creatinine clearance <50 mL/min). Patients with moderate renal insufficiency received 50 mg daily of JANUVIA and those with severe renal insufficiency or with ESRD on hemodialysis or peritoneal dialysis received 25 mg daily. In this study, the safety and tolerability of JANUVIA were generally similar to placebo. A small increase in serum creatinine was reported in patients with moderate renal insufficiency treated with JANUVIA relative to those on placebo. In addition, the reductions in A1C and FPG with JANUVIA compared to placebo were generally similar to those observed in other monotherapy studies. [See Clinical Pharmacology (12.3).]
14.2 Combination Therapy
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 JANUVIA 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 JANUVIA 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, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin (Table 5). Rescue glycemic therapy was used in 5% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.
Table 5: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Metformin*

JANUVIA 100 mg + Metformin Placebo + Metformin
A1C (%) N = 453 N = 224
  Baseline (mean) 8.0 8.0
  Change from baseline (adjusted mean) -0.7 -0.0
  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 JANUVIA 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 JANUVIA and metformin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo, to metformin alone, and to JANUVIA alone (Table 6, 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: JANUVIA 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%. Lipid effects were generally neutral. 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 6: Glycemic Parameters at Final Visit (24-Week Study) for Sitagliptin and Metformin, Alone and in Combination as Initial Therapy*

Placebo

Sitagliptin

(JANUVIA)

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*


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 JANUVIA 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 JANUVIA 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, JANUVIA and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 7). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of JANUVIA 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 7: Glycemic Parameters in a 52-Week Study Comparing JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin (Intent-to-Treat Population)*

JANUVIA 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 JANUVIA to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin(Per Protocol Population)* 


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 JANUVIA group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32.0%). Patients treated with JANUVIA 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 JANUVIA 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 JANUVIA 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, JANUVIA provided significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 8). Rescue therapy was used in 7% of patients treated with JANUVIA 100 mg and 14% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.
Table 8: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Add-on Combination Therapy with Pioglitazone*

JANUVIA 100 mg + Pioglitazone Placebo + Pioglitazone
A1C (%) N = 163 N = 174
  Baseline (mean) 8.1 8.0
  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 JANUVIA 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 JANUVIA 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 JANUVIA and pioglitazone provided significant improvements in A1C, FPG, and 2-hour PPG compared to pioglitazone monotherapy (Table 9). 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 JANUVIA 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). Lipid effects were generally neutral.
Table 9: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA in Combination with Pioglitazone as Initial Therapy*

JANUVIA 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 JANUVIA 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 JANUVIA 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 Week 18.
In combination with metformin and rosiglitazone, JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin and rosiglitazone (Table 10) at Week 18. At Week 54, mean reduction in A1C was -1.0% for patients treated with JANUVIA 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 JANUVIA 100 mg and 40% of patients treated with placebo. There was no significant difference between JANUVIA and placebo in body weight change.
Table 10: Glycemic Parameters at Week 18 for JANUVIA in Add-on Combination Therapy with Metformin and Rosiglitazone*

JANUVIA 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 -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 JANUVIA 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 JANUVIA 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, JANUVIA provided significant improvements in A1C and FPG compared to placebo (Table 11). In the entire study population (patients on JANUVIA in combination with glimepiride and patients on JANUVIA 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 JANUVIA 100 mg and 27% of patients treated with placebo. In this study, patients treated with JANUVIA 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 (5.3); Adverse Reactions (6.1).]
Table 11: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-On Combination Therapy with Glimepiride, with or without Metformin*

JANUVIA 100 mg
+ Glimepiride
Placebo +
Glimepiride
JANUVIA 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 JANUVIA 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 JANUVIA 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 JANUVIA 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), JANUVIA provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo (Table 12). 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 JANUVIA. [See Warnings and Precautions (5.3); Adverse Reactions (6.1).]
Table 12: Glycemic Parameters at Final Visit (24-Week Study) for JANUVIA as Add-on Combination Therapy with Insulin*

JANUVIA 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.
16 HOW SUPPLIED/STORAGE AND HANDLING
No. 6737 — Tablets JANUVIA, 25 mg, are pink, round, film-coated tablets with "221" on one side. They are supplied as follows:
NDC 0006-0221-31 unit-of-use bottles of 30
NDC 0006-0221-54 unit-of-use bottles of 90
NDC 0006-0221-28 unit dose blister packages of 100.
No. 6738 — Tablets JANUVIA, 50 mg, are light beige, round, film-coated tablets with "112" on one side. They are supplied as follows:
NDC 0006-0112-31 unit-of-use bottles of 30
NDC 0006-0112-54 unit-of-use bottles of 90
NDC 0006-0112-28 unit dose blister packages of 100.
No. 6739 — Tablets JANUVIA, 100 mg, are beige, round, film-coated tablets with "277" on one side. They are supplied as follows:
NDC 0006-0277-31 unit-of-use bottles of 30
NDC 0006-0277-54 unit-of-use bottles of 90
NDC 0006-0277-02 unit-of-use blister calendar package of 30
NDC 0006-0277-33 unit-of-use blister calendar package of 30
NDC 0006-0277-28 unit dose blister packages of 100
NDC 0006-0277-82 bottles of 1000.
Storage
Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature.]
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f85a48d0-0407-4c50-b0fa-7673a160bf01


Januvia西格列汀治疗2型糖尿病的新药:克服糖尿病治疗困境的新选择
DPP-4抑制剂的临床疗效
单药使用疗效:
DPP-4抑制剂是一类新型降糖药物,属脯氨酰寡肽酶家族细胞表面丝氨酸二肽酶,可选择性作用于DPP-4,对DPP-4具有高选择性和高亲和性,通过与DPP-4活性部位结合,升高体内活性肠促胰素水平并延长其作用时间,以葡萄糖依赖方式增加胰岛素释放并降低循环胰高血糖素水平,从而降低血糖。
一项纳入530例亚洲2型糖尿病患者的西格列汀单药安慰机对照研究显示,,西格列汀(100mg,qd)治疗18周可使患者糖化血红蛋白(HbA1C) 水平显著降低1.0%。另一项纳入206例≥65岁2型糖尿病患者的研究表明,西格列汀可较安慰剂显著降低患者HbA1C水平,最高降幅达1.6%。
联合使用疗效:
二甲双胍控制不佳患者:在中国进行的074研究随访24周结果显示,在二甲双胍(500mg,bid或850mg,bid)治疗后血糖控制不佳的2型糖尿病患者中,与安慰剂相比,加用西格列汀(100mg,qd)显著降低HbA1C、空腹血糖(FPG)和餐后血糖(PPG)水平(图1),且基线HbA1C>8.4%者HbA1C降幅更为显著(-1.1%)。此外,两药联合可减少血糖补救治疗,不增加体重,也不增加低血糖和胃肠道反应,患者耐受性好。
磺脲类药物控制不佳的患者:希曼森(Hemansen)等人在格列美脲或格列美脲联合二甲双胍治疗后血糖控制不佳患者中进行的一项研究显示,西格列汀(100mg,qd)可进一步降低此类患者HbA1C水平(图2)。
胰岛素控制不佳的患者:沃尔瑟伯(Vilsbell)等人的研究纳入641例患者(平均病程12年,74%使用中长效胰岛素,26%使用预混胰岛素,72%同时服用二甲双胍),结果显示,与安慰剂相比,西格列汀(100mg,qd)治疗24周可进一步降低此类患者的HbA1C水平(图3)。
台湾地区使用经验:
台湾研究者钱(Chien)等纳入血糖控制不佳的老年(>65岁)2型糖尿病患者的研究24周结果显示,与对照组相比,加用西格列汀组患者HbA1C水平显著降低1.35%,FPG和PPG降幅分别达38.3%和60.0%,且2组患者体重变化无显著差异。另一项韩国研究显示,血糖控制不佳的患者加用西格列汀可使HbA1C水平进一步降低1%以上,且分析认为体质指数<25kg/m2(占台湾糖尿病患者半数)、ß细胞功能较差和存在代谢综合征时西格列汀更显效。
冯(Feng)等在有2型糖尿病肾病的患者中进行的一项队列研究显示,,在原有治疗基础上,加用西格列汀治疗24周显著改善患者血糖控制,且对肾功能无显著影响,也无严重不良反应。
DPP-4抑制剂的安全性
高选择性保证药物安全:
2000年,马吉特(Marguet)等在DPP-4敲除小鼠中验证了DPP-4为糖尿病治疗靶点,但在选择药物时要考虑底物选择性,不能与DPP-4同工酶(如DPP-8或DPP-9等)发生作用,否则会产生临床不期望的结果。分析发现,现有已上市DPP-4抑制剂西格列汀、维格列汀、沙格列汀将DPP-8/9抑制一半时与将DPP-4抑制一半时所需药物浓度比值分别为>2600、<100、<100,可见西格列汀具有最高选择性;同时其对DPP-4的抑制程度最高,可达97%(维格列汀、沙格列汀分别为95%和80%),且24小时后仍可达80%以上(沙格列汀为70%,维格列汀仅12小时达80%)[欧盟药品补充保证书(EU-SPC)2010相关数据]。
总体耐受性良好:
DPP-4抑制剂低血糖风险低,优于磺脲类药物(与磺脲类联合须调整磺脲类剂量);不影响体重,优于磺脲类和塞唑烷二酮类(TZD);胃肠道耐受性良好,优于二甲双胍和糖苷酶抑制剂;目前无明确肝脏、胰、骨骼肌或肾脏安全性风险;上市后不良事件报告有胰腺炎等,但已有数据分析尚未证实该因果关系。
适应症
DPP-4抑制剂单药或联合用药均可显著降低患者HbA1C水平,且安全性良好。基于其有效性和安全性,2009年美国临床内分泌医师学会(AACE)推荐DPP-4抑制剂为2型糖尿病一线治疗药物,2010年中国2型糖尿病防治指南也将其纳入二线备选药物,推荐用于二甲双胍血糖控制不佳者,全球适应征见表。
台湾地区2011年调查显示,DPP-4抑制剂使用率已占28.2%,19.4%的糖尿病患者使用西格列汀。2010年,台湾糖尿病学会指南推荐DPP-4抑制剂为一线降糖药物。对台湾内分泌医生进行的调查显示,对于无二甲双胍禁忌症的患者,17%医生认为应与二甲双胍同时或更早应用西格列汀,62%医生认为应尽早加用西格列汀;对于有二甲双胍禁忌症的患者,65%医生认为西格列汀可直接取代二甲双胍。
DPP-4抑制剂研究和应用展望
DPP-4抑制剂潜在作用机制:
探究DPP-4的间接作用发现,DPP-4抑制剂还可能经胰高血糖素样肽-1依赖性肠-脑轴调节血糖。动物研究显示,小剂量西格列汀在不影响体循环DPP-4活性情况下,可增加小鼠迷走神经电活动,降低血糖。
DPP-4抑制剂具有心血管保护作用:
既往研究显示肠促胰素有一定心血管益处。纳入4项研究的汇总分析显示,DPP-4抑制剂不增加2型糖尿病患者心血管风险。弗雷德里克(Frederic)等人的研究进一步证实DPP-4抑制剂可能有心血管保护作用,可能降低2型糖尿病患者心血管死亡、心梗或卒中风险。
前景:
随着研究深入,未来DPP-4抑制剂可能用于更广泛的人群,如糖耐量受损人群、成人1型糖尿病及年轻起病成人型糖尿病(MODY)患者。
一项在大鼠中进行的研究表明,对于胰岛细胞被链脲霉素(STZ)严重破坏的大鼠,提前或同时给予西格列汀可保护ß细胞,这一结果如能在临床试验中得到证实,也将为改善患者ß细胞功能带来新的治疗希望。

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