Sitagliptin+ Metformin
Drug Related WarningSitagliptin + Metformin
Acidosis lactic
The following outcomes have been reported in postmarketing cases of metformin-associated lactic acidosis: hypotension, hypothermia, and resistant bradyarrhythmia.
The first symptoms are frequently nonspecific and grow on gradually (eg, malaise, myalgias, respiratory discomfort, somnolence, abdominal pain)
High blood lactate levels (>5 mmol/L), metformin plasma levels typically >5 mcg/mL, anion gap acidosis (without ketonuria or ketonemia), and elevated lactate/pyruvate ratio are the characteristics of this condition.
Hepatic impairment, hypoxic states (e.g., acute congestive heart failure), excessive alcohol consumption, age ≥65, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors like topiramate), and radiological studies with contrast are risk factors.
The whole prescribing information contains steps to manage and lower risk in these high-risk categories.
If metformin-associated lactic acidosis is detected, stop treatment right away and put general supportive measures in place in a hospital; hemodialysis should start right away.
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Dipeptidyl Peptidase 4 (DPP-4) Inhibitor, Biguanide, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Germany, France and Australia.
Sitagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptidyl Peptidase-IV Inhibitors and biguanide.
The combination of Sitagliptin and Metformin is approved for treating type 2 diabetes. When metformin or lifestyle modifications alone cannot achieve glycemic control, this combination of medicines helps lower blood sugar levels in adults with type 2 diabetes mellitus.
Sitagliptin is absorbed from the gastrointestinal tract, primarily in the small intestine, and is excreted mainly unchanged in the urine. Metformin is also absorbed from the small intestine, has low protein binding, and is excreted primarily unchanged in the urine.
The common side effects of Sitagliptin + Metformin are diarrhea, nausea, vomiting, upset stomach, headache, and sore throat.
Sitagliptin + Metformin is available as tablets for convenient administration.
Sitagliptin + Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.
Sitagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptidyl Peptidase-IV Inhibitors and biguanide.
Sitagliptin: Inhibition of DPP-4 by Sitagliptin slows DPP-4 mediated inactivation of incretins like GLP-1 and GIPIncretins are released throughout the day and upregulated in response to meals as part of glucose homeostasis. Incretin inhibition is reduced, which in turn depends upon glucose concentrations and enhances insulin production and reduces glucagon release. As evidenced by a decrease in glycosylated hemoglobin (HbA1c), these actions may result in an overall improvement in blood glucose control.
The Tmax of Sitagliptin is 1-4 hours.
Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Synergistic Benefits: The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin increases insulin secretion and lowers glucagon levels, whereas the insulin sensitivity-improving drug metformin decreases hepatic glucose synthesis. Combined, they produce a dual mechanism of action that improves blood glucose regulation. Better glucose control, a lower risk of hypoglycemia, and weight neutrality are made possible by this synergistic approach, which makes it an ideal choice for the complete management of diabetes.
Data Onset of action of Sitagliptin + Metformin typically occurs within 2 to 4 hours after taking the medication.
Data duration of action of Sitagliptin + Metformin effects typically lasts about 24 hours after each dose.
The Data of Tmax (time to peak concentration) of Sitagliptin + Metformin typically around 2 to 4 hours after administration.
The Data of Cmax of Sitagliptin + Metformin is typically achieved at around 2 to 4 hours after administration.
Sitagliptin + Metformin is available in oral tablets.
Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.
As the physician recommends, take the medication orally once daily, generally with a meal.
The primary use of Sitagliptin plus Metformin is to treat type 2 diabetes. It helps those who suffer from this illness in controlling their blood sugar levels. In cases where diet and exercise alone are not sufficient to achieve glycemic control, this drug is also used as an addition. It functions by enhancing insulin sensitivity and release, which eventually lowers blood glucose levels in diabetes individuals.
Sitagliptin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Dipeptyl Peptidase-IV Inhibitors and biguanides.
Sitagliptin: Sitagliptin causes a prolonged increase in active incretin levels by inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme. Insulin synthesis and the release from pancreatic beta cells and glucagon secretion from pancreatic alpha cells are the two ways that incretin hormones (such as glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]) regulate glucose homeostasis. Reduced glucagon secretion leads to decreased hepatic glucose production. Incretin hormones are generated by the gut throughout the day under normal physiological conditions, and their levels rise in response to meals. The DPP-4 enzyme quickly renders incretin hormones inactive.
Metformin: Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, delaying intestinal glucose absorption, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization.
Sitagliptin and metformin together have several benefits for those with type 2 diabetes. Through increased sensitivity and synthesis of insulin, it lowers blood sugar levels. Combining this dual-action drug with diet and exercise can help improve glycemic control. It reduces the chance of diabetic consequences like nerve damage and cardiovascular problems by controlling blood sugar levels. It may also help with weight management, which makes it a beneficial choice for people who are obese and have diabetes.
When treatment with both sitagliptin + metformin is suitable, Sitagliptin + Metformin is recommended as an adjunct to diet and exercise to improve the glycemic control in persons with type 2 diabetes mellitus.
Limitations on Use
- Patients with type 1 diabetes or those treating diabetic ketoacidosis shouldn't use Sitagliptin + Metformin because it is ineffective in those instances.
- Patients with a history of pancreatitis have not been investigated when using Sitagliptin and Metformin together. It's unclear if taking Sitagliptin + Metformin increases the risk of pancreatitis in those who have already had the condition.
Orally: Sitagliptin + Metformin is available as a tablet that can be taken orally.
To minimize Metformin's gastrointestinal side effects, increment the dose gradually. Immediate-release should be taken with meals, while extended-release is best with an evening meal. When transitioning between immediate and extended release, keep the total daily dose of Sitagliptin and Metformin consistent, not surpassing the recommended daily limit.
The dosage and duration of treatment should be as per the treating physician's clinical judgment.
Sitagliptin + Metformin has various strengths, such as 50mg+500mg, 50mg+1000mg or 100mg+1000mg.
Sitagliptin + Metformin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
Modify dosage progressively while taking tolerability and efficacy into consideration.
Not using Metformin at the moment
Immediate release: 500 mg PO BID of Metformin and 50 mg of Sitagliptin
Extended-release: 1000 mg PO qDay metformin/100 mg sitagliptin
Increase the dosage gradually to lessen the Metformin's gastrointestinal side effects.
Metformin dosage of 2,000 mg or sitagliptin of 100 mg should not be exceeded daily.
Currently on Metformin for treatment
Immediate-release
Sitagliptin 50 mg orally BID (100 mg/day) with the amount of Metformin taken as prescribed daily.
The suggested beginning dose for people receiving metformin HCl 850 mg BID is 50 mg sitagliptin/1000 mg metformin HCl PO BID.
Extended-release
100 mg of Sitagliptin with the present daily dosage of Metformin
Starting dose recommendations for people receiving metformin HCl immediate-release (850 mg or 1000 mg oraly BID) are 100 mg sitagliptin/1000 mg metformin.
Do not take more than 2,000 mg per day of Metformin or 100 mg of Sitagliptin.
Sitagliptin + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Limit consumption of alcohol and excessive drinking, which can lead to hypoglycemia (low blood sugar)
Taking Saxagliptin + Metformin with food is usually recommended to lower the risk of gastrointestinal (GI) side effects associated with Metformin.
While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.
The dietary restriction should be individualized as per patient requirements.
Sitagliptin + Metformin may be contraindicated in the following conditions:-
- Severe hypersensitive reaction to sitagliptin/metformin, sitagliptin, or metformin (e.g., anaphylaxis, erythema)
- Severely impaired kidney function (eGFR <30 ml/min/1.73 m2)
- Metabolic acidosis, both acute and chronic, including diabetic ketoacidosis
- There have been reports of metformin-associated lactic acidosis; cases have primarily included individuals with severe renal impairment; evaluate renal function before starting medication, yearly during treatment, and more frequently in high-risk patients (e.g., elderly)
- Reports of both fatal and nonfatal hemorrhagic or necrotizing pancreatitis have been made; if pancreatitis is suspected, stop using the medication right away.
- Heart failure is also seen with other DPP-4 inhibitors; weigh the benefits and risks in people who have heart failure risk factors; monitor for symptoms. If heart failure occurs, treat it with regular medical practice and consider stopping the medication.
- There have been cases of acute renal failure that have required dialysis; evaluate renal function before starting and then regularly after that.
- Metformin may reduce vitamin B12 levels; yearly hematologic parameter monitoring; reporting of severe allergic and hypersensitive events (such as anaphylaxis, angioedema, and exfoliative skin diseases, including Stevens-Johnson syndrome); immediate cessation of medication and investigation of other possible reasons; appropriately monitor and manage.
- Severe and disabling arthralgia patients on DPP-4 inhibitors have reported experiencing arthralgia; if this is the cause of your severe joint pain, stop taking the medication.
- Bullous pemphigoid was linked to the use of DPP-4 inhibitors and necessitated hospitalization. In these cases, patients recovered with topical or systemic immunosuppressive treatment and the cessation of DPP-4 inhibitor use. Patients are advised to report the development of blisters or erosions, stop DPP-4 therapy, and see a dermatologist if a bullous pemphigoid is suspected.
Alcohol Warning
It is unsafe to consume sitagliptin + Metformin with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Sitagliptin + Metformin in breastfeeding.
Pregnancy Warning
There is insufficient scientific evidence regarding the use and safety of Sitagliptin + Metformin in pregnant populations.
Food Warning
Minimize the carbohydrate or sugary intake.
The adverse reactions related to Sitagliptin + Metformin can be categorized as:-
- Common Adverse Effects: Diarrhea, nausea, and abdominal pain
- Less Common Adverse Effects: Headache and dizziness.
- Rare Adverse Effects: Pancreatitis, hypersensitivity reactions, and liver enzyme elevations.
Reports on Postmarketing
Anaphylaxis, rash, urticaria, cutaneous vasculitis, angioedema, and exfoliative skin disorders, such as Stevens-Johnson syndrome, are examples of hypersensitivity reactions.
Inflammation of the upper respiratory tract
Increases in hepatic enzymes.
Acute pancreatitis, which includes necrotizing and hemorrhagic pancreatitis, is both deadly and nonfatal.
Gastrointestinal: vomiting and constipation
Neurological: Headache
Rhabdomyolysis
Decreased kidney function, including sudden kidney failure that may need dialysis
Back discomfort, myalgia, and limb pain
Severe disabling arthralgia
The pemphigoid bullous
Pruritus
Mouth ulceration; stomatitis
Nephritis tubulointerstitial
The clinically relevant drug interactions of Sitagliptin + Metformin are briefly summarized here:
- Cationic Drugs: Cationic drugs eliminated through renal tubular secretion, like amiloride, digoxin, morphine, and others, can potentially interact with Metformin by competing for renal tubular transport systems, requiring careful monitoring and possible dose adjustments.
- Digoxin: When 100 mg sitagliptin was co-administered for ten days, there was a slight 11% increase in the AUC and an 18% increase in the Cmax of digoxin. However, these changes are not deemed clinically significant. Digoxin, being a cationic drug, could compete with Metformin for standard renal tubular transport systems, influencing the serum concentrations of digoxin, Metformin, or both. Therefore, patients on digoxin should be monitored as needed, and no dosage adjustments are required.
- Nifedipine: According to a single-dose drug interaction study between Metformin and nifedipine in healthy, regular volunteers, co-administration of nifedipine raised the amount excreted in the urine and plasma metformin Cmax and AUC by 20% and 9%, respectively. Half-life and Tmax remained unchanged.
Metformin is better absorbed when nifedipine is used. Nifedipine was hardly affected by Metformin.
- The Use of Metformin with Other Drugs: Certain drugs, such as thiazides, corticosteroids, and others, can cause hyperglycemia and disrupt glycemic control. Metformin has minimal interactions with propranolol and ibuprofen in healthy volunteers and is less likely to interact with highly protein-bound drugs than sulfonylureas.
The most common side effects of Sitagliptin + Metformin include:
Vomiting
Infection of the upper respiratory tract
Hypoglycemia, or low blood sugar
Bloating in the stomach
Loss of appetite
Sitagliptin + Metformin should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.
There is insufficient data on pregnant women now available to determine whether drugs increase the incidence of severe birth abnormalities and miscarriages.
Metformin usage
Published research on drug use during pregnancy hasn't found a conclusive link between the substance and severe birth abnormalities or the risk of miscarriage.
Registry of Pregnancy
monitors the results of pregnancies among women who have been exposed to drugs.
Urge patients to report any medication exposure during pregnancy.
Animal data
Sitagliptin: Based on AUC, oral dosages up to 30 and 20 times, respectively, the 100-mg clinical dose were given to pregnant rats and rabbits during organogenesis without causing any adverse developmental effects.
Metformin: When given to pregnant Sprague Dawley rats and rabbits during organogenesis at dosages up to 2x and 6x, respectively, a 2000-mg clinical
Clinical considerations
Maternal risk factors for poorly managed diabetes during pregnancy include preeclampsia, spontaneous abortions, preterm birth, stillbirth, and problems during delivery.
Uncontrolled diabetes raises the chance of severe birth abnormalities, stillbirth, and morbidity associated with macrosomia in the fetus.
Males and females can get pregnant. Talk to premenopausal women about the possibility of an unplanned pregnancy because metformin medication may cause ovulation in certain anovulatory women.
- Nursing Mothers
There is no information regarding the presence of drugs in human milk, its effects on breastfed infants, or milk production.
Sitagliptin
Present in the rat milk and, therefore, may possibly present in human
Metformin
A small number of published research have reported the medication's presence in human milk.
Breastfed babies exposed to Metformin have not been found to have any adverse side effects.
The effects of the medication on milk production are unknown.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population (under 18 years)have yet to be established.
- Geriatric Use
Dosage adjustment in geriatric patients
Type 2 Diabetes Mellitus
Due to the possibility of reduced renal function, initial and maintenance dosages should be monitored.
Considering tolerability and efficacy, gradually and cautiously adjust the dosage.
Not currently on Metformin
Immediate release: 500 mg PO BID of Metformin and 50 mg of Sitagliptin
Extended release: 1000 mg PO qDay metformin/100 mg sitagliptin
Increase the dosage gradually to lessen the Metformin's gastrointestinal side effects.
Metformin dosage of 2,000 mg or sitagliptin of 100 mg should not be exceeded daily.
Currently on Metformin for treatment
Sitagliptin 50 mg PO BID (100 mg per day) with the amount of Metformin taken as prescribed daily
The suggested beginning dose for people receiving metformin HCl 850 mg BID is 50 mg sitagliptin/1000 mg metformin HCl PO BID.
Extended-release
100 mg of Sitagliptin with the present daily dosage of Metformin
Starting dose recommendations for people receiving metformin HCl immediate-release (850 mg or 1000 mg orally BID) are 100 mg sitagliptin/1000 mg metformin.
Metformin dosage of 2,000 mg or Sitagliptin of 100 mg should not be exceeded daily.
Dose Adjustment in Kidney Impairment Patient:
30-45 mL/min/1.73 m2 eGFR: Not recommended.
eGFR less than 30 mL/min/1.73 m2: not recommended.
only for extended release
If, during treatment, eGFR falls to 30-45 mL/min/1.73 m2, assess the risks and benefits of continuing medication and reduce the daily dose of the sitagliptin component to 50 mg.
Stop the medication if the eGFR falls below 30 mL/min/1.73 m2 while on therapy.
Dose Adjustment in Hepatic Impairment Patients:
Hepatic impairment: Do not administer
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Sitagliptin + Metformin.
Overconsumption of Sitagliptin + Metformin could lead to severe hypoglycemia with symptoms like sweating, shakiness, confusion, rapid heartbeat, and potential loss of consciousness.
Management
There is no specific antidote or treatment for excessive intake of Sitagliptin + Metformin. However, immediate medical attention is essential. Sitagliptin + Metformin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.
Intravenous (IV) glucose is administered to the patient to raise blood sugar levels rapidly. This may involve using dextrose solutions, such as 10% dextrose, to provide a quick source of glucose.
Supportive care may include the management of symptoms, such as providing fluids and electrolytes if necessary. In cases of severe hypoglycemia, medical professionals will closely monitor and manage the patient until their condition stabilizes.
Pharmacodynamics
Sitagliptin: By inhibiting DPP-4, sitagliptin causes a stronger insulin response to glucose, a decrease in glucagon levels, and an increase in glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
Metformin: Metformin is an antihyperglycemic medication that lowers basal and postprandial plasma glucose levels in people with type 2 diabetes, improving their glucose tolerance. Its pharmacologic modes of action are distinct from those of other oral antihyperglycemic medication groups. Metformin increases peripheral glucose uptake and utilization, which lowers intestinal glucose absorption, reduces hepatic glucose synthesis, and enhances insulin sensitivity. Metformin, unlike sulfonylureas, does not result in hyperinsulinemia or hypoglycemia in either type 2 diabetes patients or healthy persons. Metformin medication does not alter insulin secretion, although it may reduce the plasma insulin response throughout the day and insulin levels while fasting.
Pharmacokinetics
Absorption
Sitagliptin: The pharmacokinetics of sitagliptin remain unchanged when taken with or without food, as it is 87% bioavailable. In two hours, sitagliptin's plasma concentration reaches its maximum.
Metformin: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).
Bioavailability: 50-60% (Metformin [fasted])
Distribution
Sitagliptin: Volume of distribution: Approx 198 L. Plasma protein binding: 38%
Metformin: Concentrates in the liver, kidney and gastrointestinal tract. It crosses the placenta and then enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.
Protein-bound: Negligible (Metformin)
Metabolism
Sitagliptin: Sitagliptin is largely not metabolized; 79% of the dosage is eliminated as the parent molecule, unaltered, in the urine. Cytochrome p450(CYP)3A4 and, to a lesser degree, CYP2C8 mediate minor metabolic pathways. In the eighteen hours, 81% of the dose was not altered; 2% was N-sulfated to the M1 metabolite; 6% was oxidatively desaturated and cyclized to the M2 metabolite; <1% was glucuronidated at an unknown site to the M3 metabolite; <1% was carbamylated and glucuronidated to the M4 metabolite; 6% was oxidatively saturated and cyclized to the M5 metabolite; and 2% was hydroxylated at an unknown site to the M6 metabolitefive. The cis isomer of a metabolite is called M2, while the trans isomer is called M5.
Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.
Elimination
Sitagliptin: The parent molecule sitagliptin is eliminated in the urine in an amount of approximately 79% unaltered. 13% of the dosage is excreted in the feces and 87% of it in the urine.
Metformin: With a plasma elimination half-life of roughly 6.2 hours, 90% of the absorbed medication is excreted via the renal pathway during the first 24 hours following oral administration. The elimination half-life of blood is roughly 17.6 hours, indicating that the erythrocyte bulk could constitute a distribution compartment.
Therapeutic benefits of a combination of Sitagliptin + Metformin
- Blood Glucose Control: Sitagliptin + Metformin combines to lower hepatic glucose synthesis and increase insulin secretion, which in turn helps control blood glucose levels. For those with type 2 diabetes, this leads to improved glucose control.
- Weight Management: This combination is a good choice for people worried about managing their weight because, in contrast to several diabetic drugs, it is either weight-neutral or may even result in negligible weight loss.
- Low Risk of Hypoglycemia: Sitagliptin + Metformin, when administered as monotherapy, has a little chance of producing hypoglycemia or low blood sugar, which is a typical side effect in managing diabetes. Patients' risk of harmful blood sugar swings is reduced as a result. This minimizes the risk of dangerous blood sugar fluctuations for patients.
- Ji L, Han P, Wang X, Liu J, Zheng S, Jou YM, O'Neill EA, Golm GT, Engel SS, Kaufman KD, Shankar RR. A randomized clinical trial of the safety and efficacy of Sitagliptin and Metformin co-administered to the Chinese patients with type 2 diabetes mellitus. J Diabetes Investig. 2016 Sep;7(5):727-36. doi: 10.1111/jdi.12511. Epub 2016 May 19. PMID: 27181998; PMCID: PMC5009135.
- Ku EJ, et al. Four-Year Durability of Initial Combination Therapy with Sitagliptin and Metformin in the Patients with Type 2 Diabetes in Clinical Practice; COSMIC Study. PLoS One. 2015 Jun 12;10(6):e0129477. Doi: 10.1371/journal.pone.0129477. PMID: 26068661; PMCID: PMC4466580.
- Xu, W., Mu, Y., Zhao, J. et al. Efficacy and safety of Metformin and Sitagliptin based on triple antihyperglycemic therapy (STRATEGY): a multicenter, randomized, controlled, non-inferiority clinical trial. Sci. China Life Sci. 60, 225–238 (2017). https://doi.org/10.1007/s11427-016-0409-7
- He M, Deng M, Wang J, Fan P, Wang Y, Zhao X, He Y, Shi B and Sui J: Efficacy and tolerability of Sitagliptin and Metformin compared with insulin as an initial therapy for newly diagnosed diabetic patients with severe hyperglycaemia. Exp Ther Med 21: 217, 2021
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Published on: 28 Oct 2023 10:01 AM GMT