Empagliflozin + Metformin

Empagliflozin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.

The combination of empagliflozin and metformin has been approved to treat type 2 diabetes. By boosting urine glucose excretion and enhancing insulin sensitivity, this combo medicine effectively manages type 2 diabetes in adults by lowering the blood sugar levels.

Empagliflozin is rapidly absorbed from the gastrointestinal tract. It is minimally protein-bound and primarily excreted unchanged in the urine. Metformin is found in the small intestine and distributed throughout the body, not extensively bound to the plasma proteins, and is excreted unchanged in the urine.

The common side effects of Empagliflozin + Metformin are taste changes, nausea, vomiting, diarrhea, joint pain, urinary tract infections, and yeast infections.

Empagliflozin + Metformin is available as tablets for convenient administration.

Empagliflozin + Metformin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.

Empagliflozin + Metformin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and biguanides.

Empagliflozin: Around 90% of the total glucose reabsorption in the kidneys occurs in the proximal tubule and is primarily carried through SGLT2 (sodium-glucose linked co-transporter-2). Therefore, the majority of glucose that is filtered through the glomerulus is reabsorbed in the tubule. To generate a Na+ gradient inside the tubular cell, Na+/K+-ATPase on the basolateral membrane of proximal tubular cells actively pumps Na+ ions into the interstitium surrounding the tubule using ATP. By blocking this co-transport, SGLT2 on the apical membrane of these cells can increase glucosuria and decrease blood glucose levels significantly. SGLT2 uses this gradient to facilitate secondary active co-transport of both Na+ and glucose out of the filtrate, reabsorbing glucose back into the blood. By increasing glucosuria, empagliflozin, a potent inhibitor of renal SGLT2 transporters found in the kidney's proximal tubules, lowers blood sugar levels. Although the precise mechanism underlying this benefit remains unknown, empagliflozin also has cardiovascular benefits, particularly in preventing heart failure, independent of its effects on blood glucose levels. Several hypotheses have been proposed, such as the potential inhibition of the Na+/H+ exchangers (NHE) 1 in the heart and NHE3 in the proximal tubule, the reduction of pro-inflammatory adipokines and diuretic/natriuretic effects to lower blood pressure and pre-load, and the prevention of cardiac fibrosis through the suppression of pro-fibrotic markers.

Metformin: Metformin decreases hepatic glucose production, reduces glucose absorption in the intestine and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Synergistic Benefits: Metformin and empagliflozin work synergistically to manage type 2 diabetes. Empagliflozin lowers blood sugar by encouraging the body to eliminate extra sugar through urine. Metformin decreases hepatic glucose synthesis and increases insulin sensitivity. When taken as a whole, they target several facets of glucose regulation, improving glycemic control. This combination can also lower blood pressure and cause weight loss. It provides a comprehensive approach to controlling diabetes and reducing the risk of related problems by treating the condition from several perspectives.

Data Onset of action of Empagliflozin + Metformin typically occurs within hours after administration.

Data duration of action of Empagliflozin + Metformin effects generally lasts throughout the day.

The Data of Tmax (time to peak concentration) of Empagliflozin + Metformin generally reached within 1-2 hours after administration.

The Data of Cmax of Empagliflozin + Metformin is achieved within 1-2 hours following administration.

Empagliflozin + 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 or twice daily, generally with a meal.

Empagliflozin + Metformin is used to treat type 2 diabetes. By combining two distinct methods of action, it helps in the regulation of adult blood glucose levels. While metformin improves insulin sensitivity and reduces the liver's synthesis of glucose, empagliflozin promotes glucose excretion in the urine, leading to better glycemic control.

Empagliflozin: For people with type 2 diabetes, the combination drug empagliflozin + metformin provides several benefits. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors like empagliflozin promote the excretion of extra glucose through the urine, which might improve blood sugar regulation and perhaps result in weight loss. Metformin lowers the production of hepatic glucose and increases insulin sensitivity. Combined, they promote weight management, lower blood sugar, and reduce the risk of cardiovascular events.

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.

Orally: Empagliflozin + Metformin is available as a tablet that can be taken orally.

It is advised to progressively raise the metformin dose at the beginning of treatment to reduce gastrointestinal adverse effects. Take the drug along with food. Avoid breaking, crushing, dissolving, or chewing extended-release pills; instead, swallow them whole. When metformin extended-release pills are partially dissolved in the stool, as has happened with some of them, a healthcare professional should assess glycemic control. The tablet strength determines the precise dosage. Do not double the next dose if missed; instead, take it as soon as possible.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Empagliflozin + Metformin has various strengths, such as 5mg+500mg, 5mg+1000mg or 12.5 mg+500mg, 12.5 +1000, 10 mg+ 1000mg or 24mg+1000 mg.

Empagliflozin + Metformin is available in the form of Oral tablets.

Adjust the initial dosage according to the patient's existing medication schedule.

Take twice a day with meals, dividing the recommended daily dosage into two doses.

10 mg of empagliflozin per day in total

Empagliflozin may be increased to a maximum total daily dose of 25 mg in patients who can tolerate 10 mg/day, and metformin may be increased to a maximum total daily dose of 2,000 mg/day, with a progressive escalation to minimize gastrointestinal side effects to metformin, for additional glycemic control.

The recommended dose of empagliflozin is 10 mg PO qDay; however, in patients who can tolerate 10 mg once a day, the dose can be increased to 25 mg qDay for further glycemic control.

Once 2,000 mg qDay is reached, metformin may be increased to the maximum gradually to minimize gastrointestinal adverse effects.

Empagliflozin + Metformin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.

Maintain adequate fluid intake to reduce the risk of dehydration and hypotension, especially in hot weather or during vigorous physical activity.

Limit consumption of alcohol as it can increase the risk of hypoglycemia.

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.

Empagliflozin + Metformin may be contraindicated in the following conditions:-

The adverse reactions related to Empagliflozin + Metformin can be categorized as: -

Ketoacidosis

Necrotizing fasciitis of the perineum (Fournier's gangrene)

Skin reactions (e.g., rash, urticaria)

Urosepsis and pyelonephritis

Acute kidney injury

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Constipation

Angioedema

The clinically relevant drug interactions of Empagliflozin and metformin are briefly summarized here:

The most common side effects of Empagliflozin + Metformin include:

Empagliflozin + Metformin should be prudent in the following group of special populations.

Pregnancy Category C: Use with caution if the benefits outweigh the risks.

Not advised based on animal data in the second and third trimesters of pregnancy.

The limited data on drug usage in pregnant women does not provide enough evidence to establish a link between the substance and a significant risk of birth abnormalities and miscarriages.

Some anovulatory women using metformin may experience ovulation, counsel premenopausal women about the possibility of an unwanted pregnancy.

In tests conducted on animals, rats given empagliflozin throughout renal development that corresponds to the late second and third trimesters of human pregnancy saw negative changes in their kidneys.

Reversible dilatations of the renal pelvis and tubules were generated by doses less than 13 times the maximum clinical dosage.

Non-teratogenic in rats and rabbits at doses up to 300 mg/kg/day, or roughly 48 and 128 times, the maximum clinical dose of 25 mg during organogenesis,

Maternal risks of diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications are increased when diabetes is poorly controlled during pregnancy. Fetal risks of significant congenital disabilities, stillbirth, and morbidity related to macrosomia are increased when diabetes is poorly controlled.

No information is available about its presence in human milk, how it affects breastfed infants, or how it affects milk production.

The milk from lactating rats contains empagliflozin.

Human kidney development may be in danger since human kidney maturation occurs in utero and throughout the first two years of life when breastfeeding may occur.

Inform patients that using a medication combination while nursing is not advised due to the possibility of major adverse events in a breastfed newborn, including the potential that empagliflozin will impair postnatal kidney development.

In pediatric patients, ten years of age and older, the safety and efficacy of empagliflozin + metformin as an addition to diet and exercise to enhance glycemic control in type 2 diabetes mellitus have been established.

<10 years: No proven efficacy or safety

≥10 years - immediate-release tablet

Adjust the initial dosage according to the patient's existing medication schedule.

Take twice daily with meals, splitting the daily total dosage into two doses; progressively increase the dosage to lessen metformin's harmful effects on the gastrointestinal tract.

Consider necessary dosage adjustments based on effectiveness and tolerability, ensuring that the combined daily dosage of metformin 2,000 mg and empagliflozin 25 mg does not exceed this limit.

In elderly patients, particularly those who have initiated Empagliflozin + Metformin, it is essential to monitor renal function closely. As ageing can lead to reduced renal function, and metformin is primarily excreted by the kidney, careful assessment and potential dose adjustments are needed to ensure the safety and effectiveness of this combination therapy in the geriatric population. Regular renal function checks are advisable to prevent any abnormalities associated with renal function decline.

eGFR <45 mL/min/1.73 m2: Contraindicated

Lactic acidosis has been linked to the use of metformin in patients with hepatic impairment.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Empagliflozin + Metformin.

Overconsumption of Empagliflozin + Metformin could lead to hypoglycemia, nausea, vomiting, abdominal pain, weakness, confusion, and, in severe cases, unconsciousness or seizures.

There is no specific antidote for Empagliflozin + Metformin overdose, emphasizing the need for immediate medical attention. Suspected overdose warrants discontinuation of the medications. In recent overdose cases, activated charcoal can limit further absorption. Supportive care addresses symptoms through fluids, electrolyte correction, and antiemetics for nausea and vomiting. Severe hypoglycemia necessitates close monitoring until stabilization. Hemodialysis may be an option in severe overdose, especially with acute kidney injury. Timely intervention and medical supervision are imperative to manage Empagliflozin + Metformin overdose effectively and mitigate potential complications.

Empagliflozin: By stopping the kidneys from reabsorbing glucose, empagliflozin decreases blood glucose levels by increasing the quantity of glucose expelled in urine. Its comparatively extended duration of effect necessitates only one dosage per day. Regardless of blood glucose level, patients should be constantly watched for ketoacidosis signs and symptoms since empagliflozin can cause diabetic ketoacidosis even when there is no hyperglycemia. Empagliflozin may be withheld in situations of acute kidney injury or stopped in patients who develop chronic renal illness because its mechanism of action depends on the renal excretion of glucose. A sugar-rich urogenital environment produced by excessive glucose excretion raises the risk of urogenital infections in patients, both male and female. Continuously monitor for any indications of a disease.

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.

Empagliflozin: Peak plasma concentrations of empagliflozin were determined 1.5 hours after oral administration. When 25 mg of empagliflozin was administered following the consumption of a high-fat, high-calorie meal, exposure was marginally reduced; compared to the fasting state, AUC decreased by about 16% and Cmax by 37%. Empagliflozin can be taken with or without meals, and the observed impact of food on its pharmacokinetics was determined to be clinically insignificant.

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])

Empagliflozin: A population pharmacokinetic study reported an apparent steady-state volume of distribution estimate of 73.8 L. Red blood cell partitioning was roughly 36.8%, and plasma protein binding was 86.2% in healthy participants after oral [14C]-empagliflozin solution was administered.

Protein-bound: 86.2%

Red blood cell partitioning: 36.8%

Vd: 73.8 L

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)

Empagliflozin: The primary route of metabolism is glucuronidation by the uridine 5'-diphosphate-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9.No significant metabolites were detected, and the most abundant metabolites were three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic exposure of each metabolite was <10%

Metformin: Excreted unchanged in the urine and did not undergo specific hepatic metabolism (no metabolites have been found in humans) or biliary excretion.

Empagliflozin: After administering healthy participants an oral [14C]-empagliflozin solution, stools (41.2%) and urine (54.4%) eliminated about 95.6% of the drug-related radioactivity. Almost half of the drug-related radioactivity discharged in urine and most drug-related radioactivity recovered in faeces were both unmodified parent drugs.

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.