Empagliflozin + Linagliptin

Empagliflozin + Linagliptin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and Dipeptyl peptidase-4 (DPP-4) inhibitors.

The combination of empagliflozin and linagliptin is authorized for the treatment of adult type 2 diabetes mellitus to enhance glycemic control and lower the risk of cardiovascular events in the patients with established cardiovascular disease, including heart attacks and strokes.

When taken orally, empagliflozin and linagliptin are absorbed by the gastrointestinal tract. The liver is where they are mainly metabolized. Linagliptin is excreted via renal and faecal routes, whereas the kidneys primarily remove empagliflozin.

The common side effects of Empagliflozin + Linagliptin are nasal congestion, urinary tract infection, sore throat, and upper respiratory tract infection.

Empagliflozin and linagliptin are available as tablets for convenient administration.

Empagliflozin + Linagliptin is available in the United States, Canada, the United Kingdom, Germany, France and Australia following regulatory approvals.

Empagliflozin + Linagliptin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and Dipeptyl peptidase-4 (DPP-4) inhibitors.

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.

Linagliptin: The incretin hormones GLP-1 and GIP (glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide) are inactivated by the enzyme DPP-4, which is inhibited by linagliptin (dipeptidyl peptidase 4, EC 3.4.14.5). The enzyme DPP-4 breaks down these hormones quickly. Incretin hormones work together to maintain glucose homeostasis physiologically. Throughout the day, incretin secretion is at a low baseline level; levels increase as soon as a meal is consumed. GLP-1 and GIP promote insulin production and secretion from pancreatic beta cells in normal and increased blood glucose levels. Additionally, GLP-1 decreases glucagon release from pancreatic alpha cells, lowering the amount of glucose excreted from the liver. Linagliptin causes an extended rise and prolonging of active incretin levels by reversibly and highly effective binding to DPP-4. Linagliptin improves glucose homeostasis via glucose-dependently increasing insulin secretion and decreasing glucagon secretion.

Synergistic Benefits: Empagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that facilitates the elimination of excess glucose in the urine, hence lowering blood glucose levels. The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin decreases glucagon levels and increases insulin secretion. For individuals who require dual therapy to manage their diabetes, this combination of drugs is an appropriate choice because of their synergistic effects on glycemic control.

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

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

The Data of Tmax (time to peak concentration) of Empagliflozin + Linagliptin typically occurs approximately 1.5 to 2 hours after oral administration.

The Data of Cmax of Empagliflozin + Linagliptin is achieved approximately 1.5 to 2 hours after oral administration.

Empagliflozin + Linagliptin 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.

Empagliflozin: For people with type 2 diabetes, the combination drug empagliflozin + Linagliptin 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. Linagliptin 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.

Linagliptin: Linagliptin increases the quantity of insulin your body produces after a meal and reduces the amount of glucose released into the blood, which helps in the treatment of Type 2 diabetes mellitus. It lowers your body's blood glucose levels in the process.

Combining Empagliflozin and linagliptin lowers blood sugar levels, which helps with glycemic control. Linagliptin functions by increasing the release of insulin, while empagliflozin increases the excretion of glucose in the urine. When combined, they promote improved control of blood sugar. Also, lowering the chance of significant adverse cardiac events may help lose weight and provide cardiovascular advantages.

Orally: Empagliflozin + Linagliptin is available as a tablet that can be taken orally. One tablet taken, with or without food, is often the recommended dose. It is crucial to adhere to the precise dosage instructions provided by a physician since they may modify the amount under specific medical requirements. For the medicine to be as effective as possible in controlling your diabetes, make sure to take it regularly at the same time every day as prescribed by the physician.

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

Empagliflozin + Linagliptin has various strengths, such as 10mg+5mg or 25mg+5mg.

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

Ten mg/5 mg PO qDay, taken in the morning with or without meals.

If necessary and acceptable, the dosage may be increased to 25 mg/5 mg once daily.

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

Limit consumption of alcohol while using this medication, as too much intake of alcohol can increase the risk of hypoglycemia. Limit consumption of alcohol as it can increase the risk of hypoglycemia.

Drink an adequate amount of water and maintain good hydration, especially when taking medications that may increase urine production, like Empagliflozin.

While taking this combination, it is advised to 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 + Linagliptin may be contraindicated in the following conditions:-

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

Acute pancreatitis, including fatal pancreatitis.

Ketoacidosis

Perineal necrotizing fasciitis (Fournier gangrene)

Hypersensitivity responses, such as angioedema, anaphylaxis, and skin problems requiring exfoliation.

Severe and disabling arthralgia

The pemphigoid bullous

Skin responses, such as urticaria or rash

Mouth ulceration, stomatitis

Rhabdomyolysis

Acute kidney injury

Constipation

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

The most common side effects of Empagliflozin + Linagliptin include:

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

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

It is not advised to take empagliflozin during the second and third trimesters of pregnancy due to animal research demonstrating negative effects on the kidneys.

A different diabetic medication that is suitable for pregnant women should be started since poorly controlled diabetes during pregnancy carries risks for both the mother and the fetus.

In rat trials, the medication combination's component empagliflozin caused unfavourable renal alterations when given during a stage of renal development corresponding to the latter half of the second and third trimesters of human pregnancy.

Renal pelvic and tubule dilatations were reversible when doses around 13 times the maximum clinical dose were administered.

When linagliptin and empagliflozin were given to pregnant rats, no negative effects on development were detected.

It is advised to patients that therapy is not recommended during breastfeeding due to the possibility of severe adverse reactions, including the potential for empagliflozin to affect postnatal renal development in a breastfed infant. Depending on how necessary the medication is to the mother, a decision should be made regarding whether to stop nursing or to stop the medication altogether. There is no information available regarding the drug's presence in human milk, its effects on breastfed infants, or its effects on milk production.

As per FDA, safety and effectiveness in the pediatric population have not been established.

The safety and effectiveness of Empagliflozin + Linagliptin in geriatric populations, especially those aged 65 and over, are well-established.

However, there is a higher occurrence of adverse reactions associated with decreased fluid volume and impaired kidney function. Empagliflozin's osmotic diuretic effect may influence the hydration status in patients aged 75 years or older.

eGFR < 45 mL/min / 1.73 m^: No change in dosage is necessary.

eGFR 1.73 m2 / 30-45 mL/min: Avoid starting medication.

In case of end-stage renal disease (ESRD), dialysis, or eGFR < 30 mL/min/1.73 m2. Not recommended

Stopped if eGFR consistently drops to less than 45 mL/min/1.73 m2.

Hepatic impairment: No dose adjustment is required.

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

Overconsumption of Empagliflozin + Linagliptin could lead to severe hypoglycemia, excessive diuresis, dehydration, electrolyte imbalances, and kidney dysfunction.

There is no specific antidote for Empagliflozin + Linagliptin 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, it can help remove excess metformin from the bloodstream and correct kidney dysfunction.

Timely intervention and medical supervision are imperative to manage Empagliflozin + Linagliptin 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.

Linagliptin: The concentration of incretin hormones increases due to the ligand's reversible binding to DPP-4. Optimal control of glucose homeostasis is achieved by linagliptin's glucose-dependent increase in insulin secretion and decrease in glucagon secretion. Linagliptin binds specifically to DPP-4 and suppresses DPP-4 activity in vitro at doses close to those used in therapeutic exposures but not DPP-8 or DPP-9.

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.

Linagliptin: Linagliptin has an estimated 30% absolute bioavailability. A high-fat meal co-administered with linagliptin resulted in a 2-hour delay in reaching Cmax and a 15% reduction in Cmax, but no effect on AUC 0-72h was seen. Lintagliptin can be taken with or without food because there shouldn't be any clinically significant effects from Cmax and Tmax variations.

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

Linagliptin: A single 5 mg intravenous dosage of linagliptin causes about 1,110 litres of mean apparent volume of distribution at steady-state in healthy people due to tissue binding, demonstrating linagliptin's broad tissue distribution. With increasing linagliptin concentration, the plasma protein binding of linagliptin decreases, from 99% at one nmol/l to 75-89% at 30 nmol/l, showing saturation of binding to DPP-4. When DPP-4 is wholly saturated at high doses, 70–80% of linagliptin is bound to proteins other than DPP-4 in the plasma, allowing 30–20% unbound.

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%

Linagliptin: A 10 mg oral dosage of [14C] linagliptin eliminated 5% of the radioactivity in urine. The metabolism only has a little impact on how quickly linagliptin is excreted. One major metabolite was shown to be pharmacologically inactive. It hence did not contribute to the plasma DPP-4 inhibitory action of linagliptin, although at steady-state having a relative exposure of 13.3% of linagliptin.

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.

Linagliptin: Within four days after administering an oral dosage of [14C] linagliptin, 85% of the radioactivity was removed, with the remaining 15% passing through urine or faeces.

An average of 70 ml/min of renal clearance was measured at a steady state.

Half-Life: 12 hr

Terminal Half-Life: >100 hr

Enterohepatic system (80%), urine (5%)