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DPP-4 INHIBITORS -  Dipeptidyl peptidase-4 inhibitor  -  Gliptins

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Drug Monographs   top of page

Products

alogliptin -NESINA® Linagliptin - Tradjenta™
Saxagliptin - Onglyza™ Sitagliptin - Januvia®

Combination Products

JANUMET® (sitagliptin and metformin HCl) tablets JANUMET ® XR (sitagliptin and metformin HCl extended-release)
JENTADUETO® XR (linagliptin and metformin hydrochloride ER) KOMBIGLYZE XR (saxagliptin and metformin HCl ER)
OSENI® (alogliptin and pioglitazone) --®

Typical reductions in A1C values - DPP-4 INHIBITORS:

 

~ 0.74% (0.73 - 1.2)
Background

Overview

 DPP4 inhibitors - Incretin mimetics


Diabetes:  Drug Class Navigation  top of page

Secretagogues

Insulin sensitizers

Alpha-glucosidase inh

Sulfonylureas Biguanides e.g. Metformin Alpha-glucosidase Inhibitors
 Meglitinides (e.g. Prandin) Glitazones - Thiazolidinediones  

Peptide analogs

AMYLIN AGONISTS - Anti-hyperglycemic Synthetic Analogs DPP-4 INHIBITORS - Dipeptidyl peptidase-4 inhibitor -Gliptins  Glucagon-like peptide-1 (GLP-1) AGONIST - Incretin Mimetics

alogliptin -NESINA®  top of page

INDICATIONS AND USAGE
NESINA 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.

Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis.

DOSAGE AND ADMINISTRATION

•The recommended dose in patients with normal renal function or mild renal impairment is 25 mg once daily.
•Can be taken with or without food.
•Adjust dose if moderate or severe renal impairment or end-stage renal disease (ESRD).

Degree of Renal Impairment

Creatinine Clearance (mL/min)

Recommended Dosing

Moderate

geq30 to <60

12.5 mg once daily

Severe/ESRD

<30

6.25 mg once daily



DOSAGE FORMS AND STRENGTHS
Tablets: 25 mg, 12.5 mg and 6.25 mg


CONTRAINDICATIONS
History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.

Linagliptin - Tradjenta™  top of page

INDICATIONS AND USAGE:
TRADJENTA 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.

Important limitations of use:
   -Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
   -Has not been studied in combination with insulin.

DOSAGE AND ADMINISTRATION:
The recommended dose of TRADJENTA is 5 mg once daily.    TRADJENTA can be taken with or without food.

DOSAGE FORMS AND STRENGTHS:
Tablets: 5 mg


CONTRAINDICATIONS:
History of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS:
     When used with an insulin secretagogue (e.g., sulfonylurea), consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia.
     There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS:
   -Adverse reactions reported in geq5% of patients treated with TRADJENTA and more commonly than in  patients treated with placebo included nasopharyngitis.
   -Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea.
   -Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person years versus zero in 433 person years for comparator).  

To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS:
P-glycoprotein/CYP 3A4 inducer: The efficacy of TRADJENTA may be reduced when administered in combination (e.g., with rifampin). Use of alternative treatments is strongly recommended.

USE IN SPECIFIC POPULATIONS:
1] Pregnancy: There are no adequate and well-controlled studies in pregnant women. TRADJENTA tablets should be used during pregnancy only if clearly needed.
2] Nursing mothers: Caution should be exercised when TRADJENTA is administered to a nursing woman.
3] Pediatric patients: Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.
4] Renal or hepatic impairment: No dose adjustment recommended.


CLINICAL PHARMACOLOGY
Mechanism of Action:
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

Pharmacodynamics:
 Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology:
 In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100 mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5 mg dose.

Pharmacokinetics:
 The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L. Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes.

Absorption:
The absolute bioavailability of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food.

Distribution:
The mean apparent volume of distribution at steady state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at geq30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Metabolism:
Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin. Excretion Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing. Renal clearance at steady state was approximately 70 mL/min.

Saxagliptin - Onglyza™  top of page

INDICATIONS AND USAGE:
ONGLYZA is a dipeptidyl peptidase-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (Monotherapy and Combination Therapy)

Important limitations of use:
Should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.


DOSAGE AND ADMINISTRATION:
The recommended dose is 2.5 mg or 5 mg once daily taken regardless of meals.

Other: -----------------------------------------
[1 ] Patients with Renal Impairment:
No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min).

The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] leq50 mL/min). ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.    Assess renal function prior to initiation of ONGLYZA and periodically thereafter.

Creatinine clearance was estimated from serum creatinine based on the Cockcroft-Gault formula:
Cockcroft-Gault formula:
CrCl = [140 - age (years)] x weight (kg) /  [72 x serum creatinine (mg/dL)]   {x 0.85 for female patients}

[ 2 ]  Strong CYP3A4/5 Inhibitors:
The dose of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).



DOSAGE FORMS AND STRENGTHS:
Tablets: 5 mg and 2.5 mg


Combination product: Saxagliptin and Metformin (Kombiglyze™ XR)
Tablet, variable release, oral:
Kombiglyze™ XR 2.5/1000: Saxagliptin 2.5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]
Kombiglyze™ XR 5/500: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 500 mg [extended release]
Kombiglyze™ XR 5/1000: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]


CONTRAINDICATIONS:
None.


WARNINGS AND PRECAUTIONS:
When used with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.   There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.


ADVERSE REACTIONS:
1] Adverse reactions reported in geq5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.

2] Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD.

3] Hypoglycemia was reported more commonly in patients treated with the combination of ONGLYZA and sulfonylurea than in patients treated with the combination of placebo and sulfonylurea.

4] Hypersensitivity-related events (e.g., urticaria, facial edema) were reported more commonly in patients treated with ONGLYZA than in patients treated with placebo.


To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS:
Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole) significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dose to 2.5 mg once daily.


USE IN SPECIFIC POPULATIONS:
1] There are no adequate and well-controlled studies in pregnant women.

2] Safety and effectiveness of ONGLYZA in pediatric patients below the age of 18 have not been established.


CLINICAL PHARMACOLOGY:
Mechanism of Action:
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4 (DPP4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.

Pharmacodynamics:
In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.

Cardiac Electrophysiology:
In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the MRHD).

Pharmacokinetics:
The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.

No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.

Absorption:
The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. ONGLYZA may be administered with or without food.

Distribution:
The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.

Metabolism:
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite. [See Drug Interactions (7).]

Excretion:
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Because the dose of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula.

Sitagliptin - Januvia®  top of page

These highlights do not include all the information needed to use JANUVIA safely and effectively. See full prescribing information for JANUVIA.

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.


Important Limitations of Use:
JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.    JANUVIA has not been studied in patients with a history of pancreatitis.


DOSAGE AND ADMINISTRATION:
The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food.

Patients with Renal Insufficiency:
Dosage adjustment is recommended for patients with moderate or severe renal insufficiency or end-stage renal disease.

For patients with mild renal insufficiency: (creatinine clearance [CrCl] geq50 mL/min, approximately corresponding to serum creatinine levels of leq1.7 mg/dL in men and leq1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.

For patients with moderate renal insufficiency: (CrCl geq30 to <50 mL/min, approximately corresponding to serum creatinine levels of >1.7 to leq3.0 mg/dL in men and >1.5 to leq2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily.

For patients with severe renal insufficiency: (CrCl <30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and >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 hemodialysis.

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.  There have been postmarketing reports of worsening renal function in patients with renal insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.

Cockcroft-Gault formula:
CrCl = [140 - age (years)] x weight (kg) /  [72 x serum creatinine (mg/dL)]   {x 0.85 for female patients}


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.




DOSAGE FORMS AND STRENGTHS:
Tablets: 100 mg, 50 mg, and 25 mg.


CONTRAINDICATIONS:
History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema.

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.

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.

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.

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.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.


ADVERSE REACTIONS:
Adverse reactions reported in geq5% 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.

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)




CLINICAL PHARMACOLOGY:
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.

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. Co-administration 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.

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.

Combination Products   top of page

  KOMBIGLYZE XR (saxagliptin and metformin HCl ER)   top of page

These highlights do not include all the information needed to use KOMBIGLYZE XR safely and effectively. See full prescribing information for KOMBIGLYZE XR.

KOMBIGLYZE XR (saxagliptin and metformin HCl extended-release) tablets

DOSAGE AND ADMINISTRATION:
Administer once daily with the evening meal.
  -Individualize the starting dose based on the patient’s current regimen then adjust the dose based on effectiveness and tolerability.
  -Do not exceed a daily dose of 5 mg saxagliptin/2000 mg metformin HCl extended-release.
  -Swallow whole. Never crush, cut, or chew.
  -Limit the saxagliptin dose to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 inhibitors (e.g., ketoconazole).

Strong CYP3A4/5 Inhibitors:
The maximum recommended dose of saxagliptin is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). For these patients, limit the KOMBIGLYZE XR dose to 2.5 mg/1000 mg once daily.

No studies have been performed specifically examining the safety and efficacy of KOMBIGLYZE XR in patients previously treated with other antihyperglycemic medications and switched to KOMBIGLYZE XR. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.

Inform patients that KOMBIGLYZE XR tablets must be swallowed whole and never crushed, cut, or chewed. Occasionally, the inactive ingredients of KOMBIGLYZE XR will be eliminated in the feces as a soft, hydrated mass that may resemble the original tablet.

DOSAGE FORMS AND STRENGTHS:
Tablets:
5 mg saxagliptin/500 mg metformin HCl extended-release
5 mg saxagliptin/1000 mg metformin HCl extended-release
2.5 mg saxagliptin/1000 mg metformin HCl extended-release


CONTRAINDICATIONS:
[1] Renal impairment.
[2] Hypersensitivity to metformin hydrochloride.
[3] Metabolic acidosis, including diabetic ketoacidosis.
[4] Temporarily discontinue in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials.


WARNINGS AND PRECAUTIONS:
Lactic acidosis: Warn patients against excessive alcohol intake. KOMBIGLYZE XR not recommended in hepatic impairment and contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. Temporarily discontinue KOMBIGLYZE XR for surgical procedures necessitating restricted intake of food and fluids.

Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.

Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea), a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia.

Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR or any other antidiabetic drug.


ADVERSE REACTIONS:
Adverse reactions reported in >5% of patients treated with metformin extended-release and more commonly than in patients treated with placebo are: diarrhea and nausea/vomiting.

Adverse reactions reported in geq55% of patients treated with saxagliptin and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache.

Adverse reactions reported in geq55% of treatment-naive patients treated with coadministered saxagliptin and metformin and more commonly than in patients treated with metformin alone are: headache and nasopharyngitis.

Hypersensitivity-related events (e.g., urticaria, facial edema) were reported more commonly in patients treated with saxagliptin than in patients treated with placebo.

   JANUMET® (sitagliptin/metformin HCl) tablets  top of page

These highlights do not include all the information needed to use JANUMET safely and effectively. See full prescribing information for JANUMET.

Initial U.S. Approval: 2007

WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure.    Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap and elevated blood lactate.    If acidosis is suspected, discontinue JANUMET and hospitalize the patient immediately.

INDICATIONS AND USAGE:
JANUMET is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.


Important Limitations of Use:
JANUMET should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
JANUMET has not been studied in patients with a history of pancreatitis.


DOSAGE AND ADMINISTRATION:
Individualize the starting dose of JANUMET based on the patient’s current regimen.

May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin.

JANUMET should be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin.


DOSAGE FORMS AND STRENGTHS:
Tablets: 50 mg sitagliptin/500 mg metformin HCl and 50 mg sitagliptin/1000 mg metformin HCl

CONTRAINDICATIONS:
Renal dysfunction, e.g., serum creatinine geq1.5 mg/dL [males], geq1.4 mg/dL [females] or abnormal creatinine clearance.

Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

History of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components of JANUMET), such as anaphylaxis or angioedema.

Temporarily discontinue JANUMET in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials.


WARNINGS AND PRECAUTIONS:
Do not use JANUMET in patients with hepatic disease.

There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Before initiating JANUMET and at least annually thereafter, assess renal function and verify as normal.

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUMET.

Measure hematologic parameters annually.

Warn patients against excessive alcohol intake.

May need to discontinue JANUMET and temporarily use insulin during periods of stress and decreased intake of fluids and food as may occur with fever, trauma, infection or surgery.

Promptly evaluate patients previously controlled on JANUMET who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis.

When used 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.

There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin (one of the components of JANUMET), such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUMET, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET or any other anti-diabetic drug.


ADVERSE REACTIONS:
The most common adverse reactions reported in geq5% of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache.

Adverse reactions reported in geq5% of patients treated with sitagliptin in combination with sulfonylurea and metformin and more commonly than in patients treated with placebo in combination with sulfonylurea and metformin were hypoglycemia and headache.

Hypoglycemia was the only adverse reaction reported in geq5% of patients treated with sitagliptin in combination with insulin and metformin and more commonly than in patients treated with placebo in combination with insulin and metformin.

Nasopharyngitis was the only adverse reaction reported in geq5% of patients treated with sitagliptin monotherapy and more commonly than in patients given placebo.

The most common (>5%) adverse reactions due to initiation of metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.


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.

DRUG INTERACTIONS:
Cationic drugs eliminated by renal tubular secretion: Use with caution.


USE IN SPECIFIC POPULATIONS:
Safety and effectiveness of JANUMET in children under 18 years have not been established.

There are no adequate and well-controlled studies in pregnant women. To report drug exposure during pregnancy call 1-800-986-8999.

JANUMET ® XR (sitagliptin and metformin HCl extended-release) top of page


Drug:  JANUMET ® XR (sitagliptin and metformin HCl extended-release)
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)
ABBREVIATED MONOGRAPH - SEE PACKAGE INSERT.

Initial U.S. Approval:  2012

Mechanism of Action:  JANUMET XR

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

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

Metformin hydrochloride
Metformin is a biguanide that improves glycemic control in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects except in certain circumstances [see Warnings and Precautions (5.9)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

INDICATIONS AND USAGE
JANUMET XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin extended-release is appropriate. (1, 14)

Important Limitations of Use:
Not for the treatment of type 1 diabetes or diabetic ketoacidosis. (1)
Has not been studied in patients with a history of pancreatitis. (1, 5.2)

DOSAGE AND ADMINISTRATION
Individualize the starting dose of JANUMET XR based on the patient's current regimen. (2.1)
May adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin extended-release. (2.1)
Administer once daily with a meal preferably in the evening. Gradually escalate the dose to reduce the gastrointestinal side effects due to metformin. (2.1)
Maintain the same total daily dose of sitagliptin and metformin when changing between JANUMET and JANUMET XR, without exceeding the maximum recommended daily dose of 2000 mg metformin extended-release. (2.1)

DOSAGE FORMS AND STRENGTHS
JANUMET XR Tablets: 100 mg sitagliptin/1000 mg metformin HCl extended-release, 50 mg sitagliptin/500 mg metformin HCl extended-release, and 50 mg sitagliptin/1000 mg metformin HCl extended-release.

CONTRAINDICATIONS
Renal dysfunction, e.g., serum creatinine >/=1.5 mg/dL [males],  >/=1.4 mg/dL [females] or abnormal creatinine clearance. (4, 5.1, 5.4)
Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
History of a serious hypersensitivity reaction (e.g., anaphylaxis or angioedema) to JANUMET XR or to one of its components. (5.14, 6.2)

WARNINGS AND PRECAUTIONS
Lactic acidosis: Warn against excessive alcohol intake. JANUMET XR is not recommended in hepatic impairment and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. (4, 5.1, 5.3, 5.4, 5.6)

Temporarily discontinue JANUMET XR in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food or fluids. (5.1, 5.4, 5.7, 5.11)
There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis in patients treated with sitagliptin (one of the components of JANUMET XR) with or without metformin. If pancreatitis is suspected, promptly discontinue JANUMET XR. (5.2)

There have been postmarketing reports of acute renal failure in patients treated with sitagliptin with or without metformin, sometimes requiring dialysis. Before initiating JANUMET XR and at least annually thereafter, assess renal function and verify as normal. (4, 5.1, 5.4, 5.10, 6.2)

Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Measure hematologic parameters annually. (5.5, 6.1)

When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. (2.1, 5.9)
There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin, such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. In such cases, promptly stop JANUMET XR, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.14, 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. (5.15)

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUMET XR or any other anti-diabetic drug. (5.16)

JENTADUETO® XR (linagliptin and metformin hydrochloride ER)  top of page

led
Drug UPDATES:  JENTADUETO® XR (linagliptin and metformin hydrochloride ER) tablets
[Drug information  /  PDF]  
Package insert - Dosing:  Click (+) next to Dosage and Administration section (drug info link)

BOXED WARNING:
WARNING: RISK OF LACTIC ACIDOSIS


Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7.1), and Use in Specific Populations (8.6, 8.7)].

If metformin-associated lactic acidosis is suspected, immediately discontinue JENTADUETO XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].

Initial U.S. Approval:  2016

Mechanism of Action:
JENTADUETO XR
JENTADUETO XR combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with type 2 diabetes mellitus: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a member of the biguanide class.

Linagliptin
Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

Metformin
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike SUs, metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.3)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.


INDICATIONS AND USAGE:
JENTADUETO XR is a dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate (1.1)

Important limitations of use:

Not for treatment of type 1 diabetes or diabetic ketoacidosis (1.2)
Has not been studied in patients with a history of pancreatitis (1.2)


DOSAGE AND ADMINISTRATION:
See links above

HOW SUPPLIED:

DOSAGE FORMS AND STRENGTHS
Tablets:
5 mg linagliptin/1000 mg metformin hydrochloride extended-release
2.5 mg linagliptin/1000 mg metformin hydrochloride extended-release

Background   top of page

Dipeptidyl peptidase-4 (DPP-4) inhibitors:
Their mechanism of action is thought to result from increased incretin levels (GLP-1 and GIP) by inhibiting its degradation by dipeptidyl peptidase-4.    Increased incretin levels inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
 GLP-1:   glucagon-like peptide-1.
 GIP: gastric inhibitory peptide (glucose-dependent insulinotropic peptide).

Glucagon-like peptide (GLP) agonists bind to a membrane GLP receptor. As a consequence, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes, thus an analogue of GLP would not be practical.

GLP-1 analogs resulted in weight loss and had more gastrointestinal side effects, while DPP-4 inhibitors were generally weight neutral and increased risk for infection and headache, but both classes appear to present an alternative to other antidiabetic drugs.

  Both GLP-1 and GIP are rapidly inactivated by the enzyme
     dipeptidyl peptidase-4 (DPP-4).

DPP4 inhibitors - Incretin mimetics
[source]

"In one RCT comprising 206 patients aged 65 or older (mean baseline HgbA1c of 7.8%) receiving either 50 or 100 mg/d of Sitagliptin was shown to reduce HbA1c by 0.7% (combined result of both doses). A combined result of 5 RCTs enlisting a total of 279 patients aged 65 or older (mean baseline HbA1c of 8%) receiving 5 mg/d of Saxagliptin was shown to reduce HbA1c by 0.73%. A combined result of 5 RCTs enlisting a total of 238 patients aged 65 or older (mean baseline HbA1c of 8.6%) receiving 100 mg/d of Vildagliptin was shown to reduce HbA1c by 1.2%. Another set of 6 combined RCTs involving Alogliptin (not yet approved, might be released in 2012) was shown to reduce HbA1c by 0.73% in 455 patients aged 65 or older who received 12.5 or 25 mg/d of the medication."   [source]

DPP-4 inhibitors lowered hemoglobin A1C values by 0.74%, comparable to other anti-diabetic drugs.

The first agent of the class - sitagliptin - was approved by the FDA in 2006.

Examples - Drugs belonging to this class are :

1. sitagliptin (FDA approved 2006, marketed by Merck & Co. as Januvia),
2. vildagliptin (marketed in the EU by Novartis as Galvus),
3. saxagliptin (FDA approved in 2009, marketed as Onglyza),
4. linagliptin (FDA approved in 2011, marketed as Tradjenta by Eli Lilly Co and Boehringer Ingelheim),
5. dutogliptin (being developed by Phenomix Corporation), Phase III
6. gemigliptin (being developed by LG Life Sciences,Korea)
7. alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently suspended as of June 2009)

Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.


Risks and side effects:
Long-term effects of DPP-4 inhibitors on mortality and morbidity are so far inconclusive, although adverse effects, including nasopharyngitis (the common cold), headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies. Other possible adverse effects, including hypersensitivity reactions and pancreatitis, have been reported.

Although extensive long-term, preclinical studies of the major DPP-4 inhibitors have failed to show any evidence of potential to cause tumors in laboratory animals, one in vitro study has raised some questions.  [source]

References

Package insert data.

Reference(s)

National Institutes of Health, U.S. National Library of Medicine, DailyMed Database.
Provides access to the latest drug monographs submitted to the Food and Drug Administration (FDA). Please review the latest applicable package insert for additional information and possible updates.  A local search option of this data can be found here.

Disclaimer

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David F. McAuley, Pharm.D., R.Ph.  GlobalRPh Inc.
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