Antidiabetic agent

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.

Generic Name: sitagliptin (SYE-ta-GLIP-tin)Brand Name: Januvia(by-merck)

Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).

Inhibits DPP-4 selectively with no effect on DPP-8 or DDP-9 in vitro at concentrations approximating those from therapeutic dosage.

Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner. Coadministration of sitagliptin and metformin has an additive effect on active GLP-1 concentrations.

GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated) by intracellular signaling pathways involving cyclic 3′,5′-adenosine monophosphate (cAMP).

GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.

Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.

Sitagliptin usually not associated with hypoglycemia or substantial changes in body weight.1

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Used in combination with metformin (given separately or as the fixed combination) as initial therapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate.

Used in combination with other oral antidiabetic agents (e.g., metformin, a sulfonylurea, a thiazolidinedione [peroxisome proliferator-activated receptor-γ agonist]) or insulin as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have not achieved adequate glycemic control with one or more oral antidiabetic agents and/or insulin.

Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones released in response to a meal. By preventing GLP-1 and GIP inactivation, they are able to increase the secretion of insulin and suppress the release of glucagon by the alpha cells of the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents.

Sitagliptin has been shown to lower HbA1c level by about 0.7% points versus placebo. It is slightly less effective than metformin when used as a monotherapy. It does not cause weight gain and has less hypoglycemia compared to sulfonylureas. Sitagliptin is recommended as a second line drug (in combination with other drugs) after the combination of diet/exercise and metformin fails.

Adults

Diabetes Mellitus

Oral

Sitagliptin monotherapy: Maximum 100 mg daily.

Fixed combination with metformin hydrochloride: Maximum 100 mg of sitagliptin and 2 g of metformin hydrochloride daily (in divided doses

Hepatic Impairment

No dosage adjustments necessary in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9). Efficacy and safety not established in patients with severe hepatic impairment (Child-Pugh score >9).

Sitagliptin Monotherapy

Oral

Moderate renal impairment (Clcr of 30 to <50 mL/minute, corresponding to Scr of >1.7–3 mg/dL in men or >1.5–2.5 mg/dL in women): 50 mg once daily.

Severe renal impairment (Clcr <30 mL/minute, corresponding to Scr of >3 mg/dL in men or >2.5 mg/dL in women): 25 mg once daily.

End-stage renal disease requiring hemodialysis or peritoneal dialysis: 25 mg once daily.

May administer without regard to timing of dialysis.

Sitagliptin monotherapy: Select dosage with caution because of age-related decreases in renal function

Absorption

Bioavailability

Absolute bioavailability 87%.

Rapidly absorbed following oral administration; at steady state (within 3 days of therapy initiation), peak plasma concentrations generally attained ≤3 hours following administration of recommended doses.

Fixed-combination tablet containing sitagliptin 50 mg and metformin hydrochloride 500 mg or 1 g (Janumet) bioequivalent to one 50-mg tablet of sitagliptin and one 500-mg or 1-g tablet of metformin hydrochloride, respectively, given simultaneously

Onset

Reduction in postprandial plasma glucose excursion: Approximately 60 minutes.

Duration

Approximately 80% inhibition of DPP-4 activity persists for 12 or 24 hours following administration of ≥50 or ≥100 mg, respectively, of sitagliptin

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.1 11

Plasma Protein Binding

38%.1

Elimination

Metabolism

Metabolized to a limited extent by CYP isoenzymes 3A4 and 2C8 to inactive metabolites.

Elimination Route

Eliminated principally by kidneys via active tubular secretion.Excreted in urine (87%) mainly as unchanged drug and in feces (13%).

Half-life

12.4 hours.

Special Populations

Renal impairment results in increased terminal elimination half-life

Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor(Pharmacokinetic analysis) in a clinical study- by

Sitagliptin was measured in plasma, urine, and dialysate samples by mass spectrometry detection following specialized high-performance liquid chromatography with an internal standard .Calculations for pharmacokinetic parameters were completed, according to established methods . The area under the sitagliptin plasma concentration curve from time 0 extrapolated to infinity (AUC0–∞) was considered the most relevant pharmacokinetic parameter because it provides an estimate of the plasma drug exposure at steady state

B sitagliptin dose adjustments are recommended for patients with moderate or severe RI or ESRD to provide plasma sitagliptin exposure comparable to patients with normal renal function. The recommended sitagliptin dosage adjustments are as follows: no adjustment for patients with mild RI (creatinine clearance 50–80 ml/min), a twofold decrease in the clinical dose of 100 mg q.d. (i.e., 50 mg q.d.) for patients with moderateRI (creatinine clearance 30–50 ml/min) (approximate serum creatinine levels >1.7 and ≤3.0 mg/dl for men and >1.5 and ≤2.5 mg/dl for women), and a fourfold decrease in the clinical dose (25 mg q.d.) for patients with severe RI (creatinine clearance <30 ml/min) or ESRD (approximate serum creatinine levels >3.0 mg/dl for men, >2.5 mg/dl for women, or on dialysis). Moreover, since hemodialysis removed sitagliptin to a modest extent, sitagliptin can be administered without respect to the timing of hemodialysis in patients with ESRD.

To conduct an open label, randomized clinical trial to treat infertility due to PCOD with combination therapy of metformin and sitagliptin.

RATIONALE: Sitagliptin help to treat infertility due to pcod by weight loss along with treating metabolic disorder.

Study design: open label

Primary purpose: to treat.

Eligibility criteria: females with pcod already on metformin oral therapy from two years.

No weight loss since taking metformin only.

Study duration 6 months.

outcome: healthy weight loss, reduced bmi, regular menstruation cycle, reduced pelvic imflamation, improvement in blood glucose levels ,over all life style improvement.

Results: …………………………………..?

Since PCOS is associated with infertility and metabolic disorder ,some- times leading to poor blood Glucose controls and high HDL , along with hormonal imbalance. Thus to treat first line of treatment is metformin .But in patients with BMI greater than 37kg/m2 it some times fails to produce results. I propose that sitagliptin can be used as monotherapy or in combination with metformin . This may increase insulin sensitivity, may address metabolic disorder leading to over all life style improvement which may increase the chances of fertility (before hormonal treatment is prescribed).